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Ballerini M, Galiè S, Tyagi P, Catozzi C, Raji H, Nabinejad A, Macandog ADG, Cordiale A, Slivinschi BI, Kugiejko KK, Freisa M, Occhetta P, Wargo JA, Ferrucci PF, Cocorocchio E, Segata N, Vignati A, Morgun A, Deleidi M, Manzo T, Rasponi M, Nezi L. A gut-on-a-chip incorporating human faecal samples and peristalsis predicts responses to immune checkpoint inhibitors for melanoma. Nat Biomed Eng 2025:10.1038/s41551-024-01318-z. [PMID: 39939548 DOI: 10.1038/s41551-024-01318-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Accepted: 11/18/2024] [Indexed: 02/14/2025]
Abstract
Patient responses to immune checkpoint inhibitors can be influenced by the gastrointestinal microbiome. Mouse models can be used to study microbiome-host crosstalk, yet their utility is constrained by substantial anatomical, functional, immunological and microbial differences between mice and humans. Here we show that a gut-on-a-chip system mimicking the architecture and functionality of the human intestine by including faecal microbiome and peristaltic-like movements recapitulates microbiome-host interactions and predicts responses to immune checkpoint inhibitors in patients with melanoma. The system is composed of a vascular channel seeded with human microvascular endothelial cells and an intestinal channel with intestinal organoids derived from human induced pluripotent stem cells, with the two channels separated by a collagen matrix. By incorporating faecal samples from patients with melanoma into the intestinal channel and by performing multiomic analyses, we uncovered epithelium-specific biomarkers and microbial factors that correlate with clinical outcomes in patients with melanoma and that the microbiome of non-responders has a reduced ability to buffer cellular stress and self-renew. The gut-on-a-chip model may help identify prognostic biomarkers and therapeutic targets.
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Affiliation(s)
- Mattia Ballerini
- Department of Experimental Oncology, Istituto Europeo di Oncologia - IRCCS (IEO), Milan, Italy
- Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy
| | - Serena Galiè
- Department of Experimental Oncology, Istituto Europeo di Oncologia - IRCCS (IEO), Milan, Italy
| | - Punit Tyagi
- Department of Experimental Oncology, Istituto Europeo di Oncologia - IRCCS (IEO), Milan, Italy
| | - Carlotta Catozzi
- Department of Experimental Oncology, Istituto Europeo di Oncologia - IRCCS (IEO), Milan, Italy
| | - Hariam Raji
- Mechanisms and Therapy of Genetic Brain Diseases, Institut Imagine, INSERM UMR1163, Université Paris Cité, Paris, France
| | - Amir Nabinejad
- Department of Experimental Oncology, Istituto Europeo di Oncologia - IRCCS (IEO), Milan, Italy
| | - Angeli D G Macandog
- Department of Experimental Oncology, Istituto Europeo di Oncologia - IRCCS (IEO), Milan, Italy
| | - Alessandro Cordiale
- Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy
| | - Bianca Ionela Slivinschi
- Mechanisms and Therapy of Genetic Brain Diseases, Institut Imagine, INSERM UMR1163, Université Paris Cité, Paris, France
| | - Karol K Kugiejko
- Department of Experimental Oncology, Istituto Europeo di Oncologia - IRCCS (IEO), Milan, Italy
- Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy
| | - Martina Freisa
- Department of Experimental Oncology, Istituto Europeo di Oncologia - IRCCS (IEO), Milan, Italy
| | - Paola Occhetta
- Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy
| | - Jennifer A Wargo
- Department of Surgical Oncology, Division of Surgery and Department of Genomic Medicine, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Pier F Ferrucci
- Dipartimento di Oncologia Interpresidio Gruppo Multimedica IRCCS, Milan, Italy
| | - Emilia Cocorocchio
- Department of Experimental Oncology, Istituto Europeo di Oncologia - IRCCS (IEO), Milan, Italy
- Humanitas-Gavazzeni, Medical Oncology, Bergamo, Italy
| | - Nicola Segata
- Department of Experimental Oncology, Istituto Europeo di Oncologia - IRCCS (IEO), Milan, Italy
- Department CIBIO, University of Trento, Trento, Italy
| | - Andrea Vignati
- Department of Experimental Oncology, Istituto Europeo di Oncologia - IRCCS (IEO), Milan, Italy
| | - Andrey Morgun
- College of Pharmacy, Oregon State University, Corvallis, OR, USA
| | - Michela Deleidi
- Mechanisms and Therapy of Genetic Brain Diseases, Institut Imagine, INSERM UMR1163, Université Paris Cité, Paris, France
| | - Teresa Manzo
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin, Italy
| | - Marco Rasponi
- Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy
| | - Luigi Nezi
- Department of Experimental Oncology, Istituto Europeo di Oncologia - IRCCS (IEO), Milan, Italy.
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Wang X, Tian H, Chi Z, Si L, Sheng X, Hu H, Gu X, Li S, Li C, Lian B, Zhou L, Mao L, Tang B, Yan X, Wei X, Li J, Liu B, Guo J, Kong Y, Cui C. Oncolytic virus OH2 extends survival in patients with PD-1 pretreated melanoma: phase Ia/Ib trial results and biomarker insights. J Immunother Cancer 2025; 13:e010662. [PMID: 39915002 PMCID: PMC11804204 DOI: 10.1136/jitc-2024-010662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Accepted: 01/19/2025] [Indexed: 02/09/2025] Open
Abstract
BACKGROUND OH2 is an oncolytic virus derived from herpes simplex virus type 2. A phase Ia/Ib clinical trial in China was conducted in patients with unresected stage III-IV melanoma, the majority of whom had the acral type, to assess the safety and preliminary efficacy of OH2. METHODS The trial enrolled patients with histologically confirmed unresectable stage III or advanced stage IV melanoma. In phase Ia, nine patients received OH2 single-dose treatment across three dose levels (106, 107, and 108 CCID50/mL, where CCID50 represents cell culture infectious dose 50%) while six patients underwent multidose therapy. Phase Ib expanded the proposed dose. Antitumor efficacy was evaluated using the Response Evaluation Criteria in Solid Tumors and immune-RECIST guidelines. NCT04386967 is the clinical trial identifier. RESULTS All 44 patients were enrolled. OH2 was well tolerated without serious adverse events (AEs) or deaths reported. No Grade 3 or higher treatment-related AEs occurred. In phase Ia, the 1-year survival rate was 92.9% (95% CI, 59.1% to 99.0%), with a median overall survival of 28.9 months (95% CI, 12.7 to not reached). In phase Ib, 10 patients achieved immune-partial response (iPR)/partial response (PR), yielding an objective response rate (ORR) of 37.0% (95% CI, 19.4% to 57.6%), with 6 patients still responding. The rate of the durable response (PR or complete response lasting at least 6 months) was at least 29.6% (8/27). Notably, 7 of 12 III-IVM1a patients who previously received programmed cell death protein-1 (PD-1) therapy achieved iPR/PR, with an ORR of 58.3% (95% CI, 27.7% to 84.8%) and a disease control rate of 75.0% (95% CI, 42.8% to 94.5%). Biomarker analysis indicated that elevated baseline neutrophil activation state correlated with poorer clinical outcomes. A phase III clinical trial is ongoing in China (NCT05868707). CONCLUSIONS OH2 oncolytic virotherapy exhibited a favorable safety profile without dose-limiting toxicities (DLTs) and demonstrated durable antitumor efficacy in patients with melanoma, especially in those who had progressed on anti-PD-1 treatment. TRIAL REGISTRATION NUMBER ClinicalTrials.gov identifier NCT04386967.
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Affiliation(s)
- Xuan Wang
- Department of Melanoma and Sarcoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing),Peking University Cancer Hospital, Beijing, China
| | - Hui Tian
- Department of Melanoma and Sarcoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing),Peking University Cancer Hospital, Beijing, China
| | - Zhihong Chi
- Department of Melanoma and Sarcoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing),Peking University Cancer Hospital, Beijing, China
| | - Lu Si
- Department of Melanoma and Sarcoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing),Peking University Cancer Hospital, Beijing, China
| | - Xinan Sheng
- Department of Genitourinary Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Peking University CancerHospital, Beijing, China
| | - Han Hu
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Hubei University of Technology, Wuhan, Hubei, China
| | - Xiangyong Gu
- Wuhan Binhui Biopharmaceutical Co., Ltd, Wuhan, Hubei, China
| | - Siming Li
- Department of Melanoma and Sarcoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing),Peking University Cancer Hospital, Beijing, China
| | - Caili Li
- Department of Melanoma and Sarcoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing),Peking University Cancer Hospital, Beijing, China
| | - Bin Lian
- Department of Melanoma and Sarcoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing),Peking University Cancer Hospital, Beijing, China
| | - Li Zhou
- Department of Genitourinary Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Peking University CancerHospital, Beijing, China
| | - Lili Mao
- Department of Melanoma and Sarcoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing),Peking University Cancer Hospital, Beijing, China
| | - Bixia Tang
- Department of Genitourinary Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Peking University CancerHospital, Beijing, China
| | - Xieqiao Yan
- Department of Genitourinary Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Peking University CancerHospital, Beijing, China
| | - Xiaoting Wei
- Department of Melanoma and Sarcoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing),Peking University Cancer Hospital, Beijing, China
| | - Juan Li
- Department of Genitourinary Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Peking University CancerHospital, Beijing, China
| | - Binlei Liu
- Wuhan Binhui Biopharmaceutical Co., Ltd, Wuhan, Hubei, China
| | - Jun Guo
- Department of Genitourinary Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Peking University CancerHospital, Beijing, China
| | - Yan Kong
- Department of Melanoma and Sarcoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing),Peking University Cancer Hospital, Beijing, China
| | - Chuanliang Cui
- Department of Genitourinary Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Peking University CancerHospital, Beijing, China
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Misawa K, Bhat H, Adusumilli PS, Hou Z. Combinational CAR T-cell therapy for solid tumors: Requisites, rationales, and trials. Pharmacol Ther 2025; 266:108763. [PMID: 39617146 PMCID: PMC11848936 DOI: 10.1016/j.pharmthera.2024.108763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 11/18/2024] [Accepted: 11/26/2024] [Indexed: 12/10/2024]
Abstract
Chimeric antigen receptor (CAR) T-cell therapy has achieved potent antitumor efficacy in hematological malignancies; however, because of limitations in CAR T-cell recruitment, infiltration, activation, and functional persistence in the tumor, its efficacy in solid tumors has been suboptimal. To overcome these challenges, combinational strategies that include chemotherapy, radiation therapy, or immune checkpoint inhibitor agent therapy with CAR T-cell therapy are being investigated. The established functional characteristics of the abovementioned therapies provide a rationale for the use of a combinational approach with CAR T cells. Chemotherapy reshapes the peritumoral stroma, decreases the immunosuppressive cell population, and promotes a proinflammatory milieu, all of which allow for increased recruitment, infiltration, and accumulation of CAR T cells. Radiation therapy promotes a chemokine gradient, which augments tumor infiltration by CAR T cells and further increases expression of tumor-associated antigens, allowing for increased activation of CAR T cells. Immune checkpoint inhibitor agent therapy inactivates T-cell exhaustion pathways-most notably, the PD1/PDL1 pathway-thereby improving the functional persistence of CAR T cells and promoting endogenous immunity. In this review, we discuss the requisites and rationales for combinational therapy, and we review 25 ongoing phase I and II clinical trials, of which 4 use chemotherapy, 3 use radiation therapy, 11 use immunotherapy, and 7 use another agent. While safety, efficacy, and improved outcomes are the primary goals of these ongoing studies, the knowledge gained from them will help pave the way for subsequent studies focused on optimizing combinational regimens and identifying predictive biomarkers.
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Affiliation(s)
- Kyohei Misawa
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
| | - Hina Bhat
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
| | - Prasad S Adusumilli
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
| | - Zhaohua Hou
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
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Zhang Y, Chen H, Mo H, Zhao N, Sun X, Liu B, Gao R, Xu B, Zhang Z, Liu Z, Ma F. Distinct cellular mechanisms underlie chemotherapies and PD-L1 blockade combinations in triple-negative breast cancer. Cancer Cell 2025:S1535-6108(25)00025-X. [PMID: 39919737 DOI: 10.1016/j.ccell.2025.01.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Revised: 11/05/2024] [Accepted: 01/13/2025] [Indexed: 02/09/2025]
Abstract
Combining immune checkpoint blockade (ICB) with chemotherapy shows promise for treating triple-negative breast cancer (TNBC), though the mechanisms remain incompletely understood. Here, we integrate published and new single-cell RNA sequencing (scRNA-seq) data to investigate the tumor immune microenvironment (TIME) in TNBC patients treated with paclitaxel (PTX), nab-paclitaxel (Nab-PTX), and their combinations with the anti-PD-L1 antibody atezolizumab (ATZ). Compared to ATZ plus PTX, ATZ plus Nab-PTX rewires TCF7+ stem-like effector memory CD8+ T cells (Tsem) and CD4+ T follicular helper (Tfh) cells. Nab-paclitaxel, unlike PTX, also reshapes the myeloid compartment, expanding mast cells and pro-inflammatory macrophages. Our analyses in human TNBC and murine models underscore the crucial role of mast cells in orchestrating anti-tumor immune responses, likely by promoting the recruitment and activation of T and B cells. In vivo experiments demonstrate that activating mast cells alongside PD-L1 blockade attenuates TNBC progression, suggesting mast cells as a promising adjunct for enhancing ICB therapy efficacy.
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Affiliation(s)
- Yuanyuan Zhang
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; BIOPIC, Beijing Advanced Innovation Center for Genomics, School of Life Sciences, Peking University, Beijing 100871, China.
| | - Hongyan Chen
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Hongnan Mo
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Ning Zhao
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Xiaoying Sun
- Department of Medical Oncology, Cancer Hospital of HuanXing, ChaoYang District, Beijing 100005, China
| | - Baolin Liu
- BIOPIC, Beijing Advanced Innovation Center for Genomics, School of Life Sciences, Peking University, Beijing 100871, China
| | - Ranran Gao
- BIOPIC, Beijing Advanced Innovation Center for Genomics, School of Life Sciences, Peking University, Beijing 100871, China
| | - Binghe Xu
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
| | - Zemin Zhang
- BIOPIC, Beijing Advanced Innovation Center for Genomics, School of Life Sciences, Peking University, Beijing 100871, China.
| | - Zhihua Liu
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
| | - Fei Ma
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
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5
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Leshem R, Sefton KN, Wong CW, Lin IH, Isaac DT, Niepel M, Hurlstone A. Combined PARP14 inhibition and PD-1 blockade promotes cytotoxic T cell quiescence and modulates macrophage polarization in relapsed melanoma. J Immunother Cancer 2025; 13:e010683. [PMID: 39870492 PMCID: PMC11772928 DOI: 10.1136/jitc-2024-010683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Accepted: 01/09/2025] [Indexed: 01/29/2025] Open
Abstract
BACKGROUND Programmed cell death 1 (PD-1) signaling blockade by immune checkpoint inhibitors (ICI) effectively restores immune surveillance to treat melanoma. However, chronic interferon-gamma (IFNγ)-induced immune homeostatic responses in melanoma cells contribute to immune evasion and acquired resistance to ICI. Poly ADP ribosyl polymerase 14 (PARP14), an IFNγ-responsive gene product, partially mediates IFNγ-driven resistance. PARP14 inhibition prolongs PD-1 blockade responses in preclinical models, but fails to achieve full tumor clearance, suggesting the involvement of additional resistance mechanisms. METHODS We identified a robust PARP14 catalytic inhibitor gene signature and evaluated its association with patient survival. Using preclinical models and single-cell RNA sequencing, we investigated immune and tumor cell adaptations to PARP14 inhibition combined with PD-1 blockade. RESULTS Combining PARP14 inhibition and PD-1 blockade suppressed tumor-associated macrophages while increasing proinflammatory memory macrophages. Moreover, this combination mitigated the terminal exhaustion of cytotoxic T cells by inducing a quiescent state, thereby preserving functionality. Despite the enhanced immune responses, tumor cells developed adaptive resistance by engaging alternative immune evasion pathways. CONCLUSIONS Although adaptive resistance mechanisms re-emerge, PARP14 inhibition combined with PD-1 blockade offers a promising strategy to enhance treatment outcomes and overcome ICI resistance in melanoma, as immune cells are primed for further therapeutic interventions that leverage the quiescent state.
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Affiliation(s)
- Rotem Leshem
- Division of Infection, Immunity and Respiratory Medicine, The University of Manchester, Manchester, UK
- Lydia Becker Institute of Immunology and Inflammation, The University of Manchester, Manchester, UK
- School of Biological Sciences, The University of Manchester, Manchester, UK
| | - Kieran Neil Sefton
- Division of Infection, Immunity and Respiratory Medicine, The University of Manchester, Manchester, UK
- Lydia Becker Institute of Immunology and Inflammation, The University of Manchester, Manchester, UK
- School of Biological Sciences, The University of Manchester, Manchester, UK
| | - Chun Wai Wong
- Division of Infection, Immunity and Respiratory Medicine, The University of Manchester, Manchester, UK
- Lydia Becker Institute of Immunology and Inflammation, The University of Manchester, Manchester, UK
- School of Biological Sciences, The University of Manchester, Manchester, UK
- Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - I-Hsuan Lin
- Bioinformatics Core Facility, The University of Manchester, Manchester, UK
| | | | - Mario Niepel
- Ribon Therapeutics, Cambridge, Massachusetts, USA
| | - Adam Hurlstone
- Division of Infection, Immunity and Respiratory Medicine, The University of Manchester, Manchester, UK
- Lydia Becker Institute of Immunology and Inflammation, The University of Manchester, Manchester, UK
- School of Biological Sciences, The University of Manchester, Manchester, UK
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Mok S, Liu H, Ağaç Çobanoğlu D, Anang NAAS, Mancuso JJ, Wherry EJ, Allison JP. Anti-CTLA-4 generates greater memory response than anti-PD-1 via TCF-1. Proc Natl Acad Sci U S A 2025; 122:e2418985122. [PMID: 39786926 PMCID: PMC11745370 DOI: 10.1073/pnas.2418985122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Accepted: 12/10/2024] [Indexed: 01/12/2025] Open
Abstract
The effects of T cell differentiation arising from immune checkpoint inhibition targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) on the immunological memory response remain unclear. Our investigation into the effects of anti-CTLA-4 and anti-PD-1 on memory T cell formation in mice reveals that memory T cells generated by anti-CTLA-4 exhibit greater expansion, cytokine production, and antitumor activity than those from anti-PD-1. Notably, anti-CTLA-4 preserves more T cell factor-1 (TCF-1)+ T cells during priming, while anti-PD-1 leads to more thymocyte selection-associated high mobility group box (TOX)+ T cells. Experiments using conditional Tcf7- or Tox-knockout mice highlight that TCF-1 is essential for the memory response generated by anti-CTLA-4, whereas TOX deletion alone in T cells has no effect on the response to anti-PD-1. Deepening our understanding of how checkpoint inhibition affects memory response is crucial for advancing our understanding of the enduring impacts of these immunotherapies on the immune system.
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Affiliation(s)
- Stephen Mok
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX77030
| | - Huey Liu
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX77030
| | - Didem Ağaç Çobanoğlu
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX77030
| | - Nana-Ama A. S. Anang
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX77030
| | - James J. Mancuso
- James P. Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, TX77030
| | - E. John Wherry
- Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA19104
| | - James P. Allison
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX77030
- James P. Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, TX77030
- Parker Institute for Cancer Immunotherapy, The University of Texas MD Anderson Cancer Center, Houston, TX77030
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7
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Liu Q, Xing H, Xiong M, Zhang XB. Specifically Editing Cancer Sialoglycans for Enhanced In Vivo Immunotherapy through Aptamer-Enzyme Chimeras. Angew Chem Int Ed Engl 2025; 64:e202414327. [PMID: 39324841 DOI: 10.1002/anie.202414327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 09/26/2024] [Accepted: 09/26/2024] [Indexed: 09/27/2024]
Abstract
Immune checkpoint blockade (ICB) therapies have demonstrated remarkable clinical success in treating cancer. However, their objective response rate remains suboptimal because current therapies rely on limited immune checkpoints that fail to cover the multiple immune evasion pathways of cancer. To explore potential ICB strategies, we propose a glycoimmune checkpoint elimination (glycoICE) therapy based on targeted editing of sialoglycans on the tumor cell surface using an aptamer-enzyme chimera (ApEC). The ApEC can be readily generated via a one-step bioorthogonal procedure, allowing for large-scale and uniform production. It specifically targets and desialylates cancer cells, disrupting the sialoglycan-Siglec axis to activate immune cells and enhance immunotherapy efficacy, while its high tumor selectivity minimizes side effects from indiscriminate desialylation of normal tissues. Furthermore, the ApEC has the potential to be a versatile platform for specific editing of sialoglycans in different tumor models by adjusting the aptamer sequences to target specific protein markers. This research not only introduces a novel molecular tool for the effective editing of sialoglycans in complex environments, but also provides valuable insights for advancing DNA-based drugs towards in vivo and clinical applications.
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Affiliation(s)
- Qin Liu
- Molecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, 410082, Changsha, Hunan, P. R. China
| | - Hang Xing
- Institute of Chemical Biology and Nanomedicine, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, 410082, Changsha, Hunan, P. R. China
| | - Mengyi Xiong
- Molecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, 410082, Changsha, Hunan, P. R. China
| | - Xiao-Bing Zhang
- Molecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, 410082, Changsha, Hunan, P. R. China
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8
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Barham WT, Stagg MP, Mualla R, DiLeo M, Kansara S. Recurrent and Metastatic Head and Neck Cancer: Mechanisms of Treatment Failure, Treatment Paradigms, and New Horizons. Cancers (Basel) 2025; 17:144. [PMID: 39796771 PMCID: PMC11720666 DOI: 10.3390/cancers17010144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 12/21/2024] [Accepted: 01/03/2025] [Indexed: 01/13/2025] Open
Abstract
Background: Head and neck cancer is a deadly disease with over 500,000 cases annually worldwide. Metastatic head and neck cancer accounts for a large proportion of the mortality associated with this disease. Many advances have been made in our understanding of the mechanisms of metastasis. The application of immunotherapy to locally recurrent or metastatic head and neck cancer has not only improved oncologic outcomes but has also provided valuable insights into the mechanisms of immune evasion and ultimately treatment failure. Objectives: This review paper will review our current understanding of biological mechanisms of treatment failure and metastasis. Published and ongoing clinical trials in the management of metastatic head and neck cancer will also be summarized. Methods: A narrative review was conducted to address the current understanding of the mechanisms of treatment failure and current treatment paradigms in recurrent and metastatic head and neck carcinoma. Conclusions: Our understanding of treatment failure in this disease is rapidly evolving. Immunotherapy represents a valuable new tool in the fight against recurrent and metastatic head and neck squamous cell carcinoma. Integrating patient and tumor specific data via artificial intelligence and deep learning will allow for a precision oncology approach, thereby achieving better prognostication and management of patients with this deadly disease.
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Affiliation(s)
- William T. Barham
- Department of Otolaryngology-Head and Neck Surgery, Louisiana State University Health Sciences Center, New Orleans, LA 71103, USA; (W.T.B.); (R.M.); (M.D.)
| | - Marshall Patrick Stagg
- Department of Oncology, Our Lady of the Lake Regional Medical Center, Baton Rouge, LA 70809, USA;
| | - Rula Mualla
- Department of Otolaryngology-Head and Neck Surgery, Louisiana State University Health Sciences Center, New Orleans, LA 71103, USA; (W.T.B.); (R.M.); (M.D.)
| | - Michael DiLeo
- Department of Otolaryngology-Head and Neck Surgery, Louisiana State University Health Sciences Center, New Orleans, LA 71103, USA; (W.T.B.); (R.M.); (M.D.)
| | - Sagar Kansara
- Department of Otolaryngology-Head and Neck Surgery, Louisiana State University Health Sciences Center, New Orleans, LA 71103, USA; (W.T.B.); (R.M.); (M.D.)
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Garg S, Rai G, Singh S, Gauba P, Ali J, Dang S. An insight into the role of innate immune cells in breast tumor microenvironment. Breast Cancer 2025; 32:79-100. [PMID: 39460874 DOI: 10.1007/s12282-024-01645-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 10/21/2024] [Indexed: 10/28/2024]
Abstract
The immune background of breast cancer is highly heterogeneous and the immune system of the human body plays a dual role by both promoting and suppressing its progression. Innate immune cells are the first line of defense in the immune system and impart protection by identifying and interacting with foreign pathogens and cancer cells. Different innate immune cells like natural killer cells, macrophages, dendritic cells, and myeloid suppressor cells take part in hosting the cancer cells. Autophagy is another key component inside the tumor microenvironment and is linked to the disintegration and recycling of cellular components. Within the tumor microenvironment autophagy is involved with Pattern Recognition Receptors and inflammation. Various clinical studies have shown prominent results where innate immune cells and autophagy in combination are used for pathogen as well as cancer cell clearance. However, it is necessary to comprehend the complex tumor microenvironment so that different therapeutic approaches can be developed to enhance the suppressive actions of the cells toward breast cancer cells. In this review article, the complex interaction between immune cells and breast cancer cells and their role in developing effective immunotherapies to improve patient outcomes are discussed in detail.
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Affiliation(s)
- Sandini Garg
- Department of Biotechnology, Jaypee Institute of Information Technology, Noida, Uttar Pradesh, India
| | - Garima Rai
- Department of Biotechnology, Jaypee Institute of Information Technology, Noida, Uttar Pradesh, India
| | - Sakshi Singh
- Department of Biotechnology, Jaypee Institute of Information Technology, Noida, Uttar Pradesh, India
| | - Pammi Gauba
- Department of Biotechnology, Jaypee Institute of Information Technology, Noida, Uttar Pradesh, India
| | - Javed Ali
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Shweta Dang
- Department of Biotechnology, Jaypee Institute of Information Technology, Noida, Uttar Pradesh, India.
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10
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Zheng DX, Bozym DJ, Tarantino G, Sullivan RJ, Liu D, Jenkins RW. Overcoming Resistance Mechanisms to Melanoma Immunotherapy. Am J Clin Dermatol 2025; 26:77-96. [PMID: 39636504 DOI: 10.1007/s40257-024-00907-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/05/2024] [Indexed: 12/07/2024]
Abstract
The advent of immune checkpoint inhibition has revolutionized treatment of advanced melanoma. While most patients derive survival benefit from established immunotherapies, notably monoclonal antibodies blocking cytotoxic T-lymphocyte antigen 4 and programmed cell death protein 1, a subset does not optimally respond due to the manifestation of innate or acquired resistance to these therapies. Combination regimens have proven efficacious relative to single-agent blockade, but also yield high-grade treatment toxicities that are often dose-limiting for patients. In this review, we discuss the significant strides made in the past half-decade toward expanding the melanoma immunotherapy treatment paradigm. These include newly approved therapies, adoption of neoadjuvant immunotherapy, and studies in the clinical trials pipeline targeting alternative immune checkpoints and key immunoregulatory molecules. We then review how developments in molecular and functional diagnostics have furthered our understanding of the tumor-intrinsic and -extrinsic mechanisms driving immunotherapy resistance, as well as highlight novel biomarkers for predicting treatment response. Throughout, we discuss potential approaches for targeting these resistance mechanisms in rational combination with established immunotherapies to improve outcomes for patients with melanoma.
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Affiliation(s)
- David X Zheng
- Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - David J Bozym
- Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Giuseppe Tarantino
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Ryan J Sullivan
- Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - David Liu
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Russell W Jenkins
- Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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11
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Ali MS, Ahn J, Espat NJ, Calvino AS, Koness J, Somasundar P, Kwon S. Disparities in utilization of novel cancer therapies in advanced stage III and IV melanoma and variance in outcomes. Immunotherapy 2025; 17:37-46. [PMID: 39825755 PMCID: PMC11834448 DOI: 10.1080/1750743x.2025.2452836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Accepted: 01/09/2025] [Indexed: 01/20/2025] Open
Abstract
INTRODUCTION Significant gains in advanced melanoma have been made through immunotherapy trials. Factors influencing equitable access and survival impact of these novel therapies are not well-defined. METHOD Retrospective analysis using National Cancer Database of patients with advanced stage III and IV melanoma from 2004 to 2021. Multivariable logistic regression was used to study the use of immunotherapy and Cox proportional hazard regression to evaluate overall survival (OS). RESULTS 47,427 patients with increasing utilization of immunotherapy from 13.78% in 2004 to 65.88% by 2021. Inequitable adoption were impacted by age, sex, socioeconomic status/affordability, insurance types and residential educational/income level. Receiving immunotherapy was associated with a 44% improvement in OS (HR 0.56, 95% CI 0.54-0.57) and receiving a clinical trial-based therapy was associated with a 37% improvement (HR 0.63, 95% CI 0.53-0.75). Among patients who received immunotherapy or clinical trial-base therapy, there was 40% worse survival in non-Hispanic Black patients (HR 1.40, 95% CI 1.16-1.69) compared to non-Hispanic Whites. CONCLUSION There are disparities in utilization of immunotherapy that is influenced by socioeconomic status. Race and ethnicity had a significant influence in differential impact on survival outcomes of immunotherapies highlighting the importance of increasing underrepresented population participation in trials that lead to novel therapies.
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Affiliation(s)
- Mohammad S. Ali
- Department of Surgery, Division of Surgical Oncology, Roger Williams Medical Center, Providence, RI, USA
- Department of Surgery, Boston University Medical Center, Boston, MA, USA
| | - Jae Ahn
- Department of Surgery, Boston University Medical Center, Boston, MA, USA
| | - N. Joseph Espat
- Department of Surgery, Division of Surgical Oncology, Roger Williams Medical Center, Providence, RI, USA
- Department of Surgery, Boston University Medical Center, Boston, MA, USA
- Department of Surgery, Roger Williams Surgery and Cancer Outcomes Research and Equity (RWSCORE) Center, Providence, RI, USA
| | - Abdul S. Calvino
- Department of Surgery, Division of Surgical Oncology, Roger Williams Medical Center, Providence, RI, USA
- Department of Surgery, Boston University Medical Center, Boston, MA, USA
- Department of Surgery, Roger Williams Surgery and Cancer Outcomes Research and Equity (RWSCORE) Center, Providence, RI, USA
| | - James Koness
- Department of Surgery, Division of Surgical Oncology, Roger Williams Medical Center, Providence, RI, USA
- Department of Surgery, Boston University Medical Center, Boston, MA, USA
| | - Ponnandai Somasundar
- Department of Surgery, Division of Surgical Oncology, Roger Williams Medical Center, Providence, RI, USA
- Department of Surgery, Boston University Medical Center, Boston, MA, USA
- Department of Surgery, Roger Williams Surgery and Cancer Outcomes Research and Equity (RWSCORE) Center, Providence, RI, USA
| | - Steve Kwon
- Department of Surgery, Division of Surgical Oncology, Roger Williams Medical Center, Providence, RI, USA
- Department of Surgery, Boston University Medical Center, Boston, MA, USA
- Department of Surgery, Roger Williams Surgery and Cancer Outcomes Research and Equity (RWSCORE) Center, Providence, RI, USA
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12
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Santiago-Sánchez GS, Fabian KP, Hodge JW. A landscape of checkpoint blockade resistance in cancer: underlying mechanisms and current strategies to overcome resistance. Cancer Biol Ther 2024; 25:2308097. [PMID: 38306161 PMCID: PMC10841019 DOI: 10.1080/15384047.2024.2308097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 01/17/2024] [Indexed: 02/03/2024] Open
Abstract
The discovery of immune checkpoints and the development of immune checkpoint inhibitors (ICI) have achieved a durable response in advanced-stage cancer patients. However, there is still a high proportion of patients who do not benefit from ICI therapy due to a lack of response when first treated (primary resistance) or detection of disease progression months after objective response is observed (acquired resistance). Here, we review the current FDA-approved ICI for the treatment of certain solid malignancies, evaluate the contrasting responses to checkpoint blockade in different cancer types, explore the known mechanisms associated with checkpoint blockade resistance (CBR), and assess current strategies in the field that seek to overcome these mechanisms. In order to improve current therapies and develop new ones, the immunotherapy field still has an unmet need in identifying other molecules that act as immune checkpoints, and uncovering other mechanisms that promote CBR.
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Affiliation(s)
- Ginette S. Santiago-Sánchez
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Kellsye P. Fabian
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - James W. Hodge
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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13
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Hegyi B, Csikó KG, Balatoni T, Fröhlich G, Bőcs K, Tóth E, Mohos A, Neumark AR, Menyhárt CD, Ferrone S, Ladányi A. Tumor-Infiltrating Immune Cells and HLA Expression as Potential Biomarkers Predicting Response to PD-1 Inhibitor Therapy in Stage IV Melanoma Patients. Biomolecules 2024; 14:1609. [PMID: 39766316 PMCID: PMC11674713 DOI: 10.3390/biom14121609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 12/09/2024] [Accepted: 12/13/2024] [Indexed: 01/11/2025] Open
Abstract
PD-1 inhibitors are known to be effective in melanoma; however, a considerable proportion of patients fail to respond to therapy, necessitating the identification of predictive markers. We examined the predictive value of tumor cell HLA class I and II expression and immune cell infiltration in melanoma patients treated with PD-1 inhibitors. Pretreatment surgical samples from 40 stage IV melanoma patients were studied immunohistochemically for melanoma cell expression of HLA class I molecules (using four antibody clones with different specificities), HLA-II, and immune cell infiltration (using a panel of 10 markers). Among the responders, the ratio of patients showing melanoma cell HLA-II expression was higher compared to non-responders (p = 0.0158), and similar results were obtained in the case of two anti-HLA-I antibodies. A combined score of HLA-I/II expression also predicted treatment response (p = 0.0019). Intratumoral infiltration was stronger in the responders for most immune cell types. Progression-free survival showed an association with HLA-II expression, the combined HLA score, and the density of immune cells expressing CD134 and PD-1, while overall survival was significantly associated only with HLA class II expression. Our findings corroborate previous results indicating the importance of immune cell infiltration and tumor cell HLA-II expression in the efficacy of PD-1 inhibitor treatment in a "real world" patient cohort and suggest the potential predictive role of HLA class I expression.
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Affiliation(s)
- Barbara Hegyi
- Department of Chest and Abdominal Tumors and Clinical Pharmacology, National Institute of Oncology, H-1122 Budapest, Hungary; (B.H.); (K.G.C.)
- National Tumor Biology Laboratory, National Institute of Oncology, H-1122 Budapest, Hungary; (T.B.); (E.T.)
- Doctoral College, Semmelweis University, H-1085 Budapest, Hungary
| | - Kristóf György Csikó
- Department of Chest and Abdominal Tumors and Clinical Pharmacology, National Institute of Oncology, H-1122 Budapest, Hungary; (B.H.); (K.G.C.)
- National Tumor Biology Laboratory, National Institute of Oncology, H-1122 Budapest, Hungary; (T.B.); (E.T.)
- Doctoral College, Semmelweis University, H-1085 Budapest, Hungary
| | - Tímea Balatoni
- National Tumor Biology Laboratory, National Institute of Oncology, H-1122 Budapest, Hungary; (T.B.); (E.T.)
- Department of Oncodermatology, National Institute of Oncology, H-1122 Budapest, Hungary
| | - Georgina Fröhlich
- Center of Radiotherapy, National Institute of Oncology, H-1122 Budapest, Hungary;
- Department of Biophysics, Eötvös Loránd University, H-1117 Budapest, Hungary
| | - Katalin Bőcs
- Department of Diagnostic Radiology, National Institute of Oncology, H-1122 Budapest, Hungary;
| | - Erika Tóth
- National Tumor Biology Laboratory, National Institute of Oncology, H-1122 Budapest, Hungary; (T.B.); (E.T.)
- Department of Surgical and Molecular Pathology, National Institute of Oncology, H-1122 Budapest, Hungary
| | - Anita Mohos
- Department of Pathology and Experimental Cancer Research, Semmelweis University, H-1085 Budapest, Hungary;
- Department of Dermatology, Venereology and Dermatooncology, Semmelweis University, H-1085 Budapest, Hungary
| | | | | | - Soldano Ferrone
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Andrea Ladányi
- National Tumor Biology Laboratory, National Institute of Oncology, H-1122 Budapest, Hungary; (T.B.); (E.T.)
- Department of Surgical and Molecular Pathology, National Institute of Oncology, H-1122 Budapest, Hungary
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14
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Sperber J, Yoo S, Owolo E, Dalton T, Zachem TJ, Johnson E, Herndon JE, Nguyen AD, Hockenberry H, Bishop B, Abu-Bonsrah N, Cook SH, Fecci PE, Sperduto PW, Johnson MO, Erickson MM, Goodwin CR. Validation of the graded prognostic assessment and recursive partitioning analysis as prognostic tools using a modern cohort of patients with brain metastases. Neurooncol Pract 2024; 11:763-771. [PMID: 39554788 PMCID: PMC11567744 DOI: 10.1093/nop/npae057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2024] Open
Abstract
Background Prognostic indices for patients with brain metastases (BM) are needed to individualize treatment and stratify clinical trials. Two frequently used tools to estimate survival in patients with BM are the recursive partitioning analysis (RPA) and the diagnosis-specific graded prognostic assessment (DS-GPA). Given recent advances in therapies and improved survival for patients with BM, this study aims to validate and analyze these 2 models in a modern cohort. Methods Patients diagnosed with BM were identified via our institution's Tumor Board meetings. Data were retrospectively collected from the date of diagnosis with BM. The concordance of the RPA and GPA was calculated using Harrell's C index. A Cox proportional hazards model with backwards elimination was used to generate a parsimonious model predictive of survival. Results Our study consisted of 206 patients diagnosed with BM between 2010 and 2019. The RPA had a prediction performance characterized by Harrell's C index of 0.588. The DS-GPA demonstrated a Harrell's C index of 0.630. A Cox proportional hazards model assessing the effect of age, presence of lung, or liver metastases, and Eastern Cooperative Oncology Group (ECOG) performance status score of 3/4 on survival yielded a Harrell's C index of 0.616. Revising the analysis with an uncategorized ECOG demonstrated a C index of 0.648. Conclusions We found that the performance of the RPA remains unchanged from previous validation studies a decade earlier. The DS-GPA outperformed the RPA in predicting overall survival in our modern cohort. Analyzing variables shared by the RPA and DS-GPA produced a model that performed analogously to the DS-GPA.
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Affiliation(s)
- Jacob Sperber
- Department of Neurosurgery, Duke University School of Medicine, Durham, North Carolina, USA
| | - Seeley Yoo
- Department of Neurosurgery, Duke University School of Medicine, Durham, North Carolina, USA
| | - Edwin Owolo
- Department of Neurosurgery, Duke University School of Medicine, Durham, North Carolina, USA
| | - Tara Dalton
- Department of Neurosurgery, Duke University School of Medicine, Durham, North Carolina, USA
| | - Tanner J Zachem
- Department of Neurosurgery, Duke University School of Medicine, Durham, North Carolina, USA
| | - Eli Johnson
- Department of Neurosurgery, Duke University School of Medicine, Durham, North Carolina, USA
| | - James E Herndon
- Department of Biostatistics & Bioinformatics, Duke University School of Medicine, Durham, North Carolina, USA
| | - Annee D Nguyen
- Department of Neurosurgery, Duke University School of Medicine, Durham, North Carolina, USA
| | - Harrison Hockenberry
- Department of Neurosurgery, Duke University School of Medicine, Durham, North Carolina, USA
| | - Brandon Bishop
- Department of Neurosurgery, Duke University School of Medicine, Durham, North Carolina, USA
- Kansas City University, Kansas City, Missouri, USA
| | - Nancy Abu-Bonsrah
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Research Department, Association of Future African Neurosurgeons, Yaounde, Cameroon
| | - Steven H Cook
- Department of Neurosurgery, Duke University School of Medicine, Durham, North Carolina, USA
| | - Peter E Fecci
- Department of Neurosurgery, Duke University School of Medicine, Durham, North Carolina, USA
| | - Paul W Sperduto
- Duke Radiation Oncology, Duke University School of Medicine, Durham, North Carolina, USA
| | - Margaret O Johnson
- Department of Neurosurgery, Duke University School of Medicine, Durham, North Carolina, USA
| | - Melissa M Erickson
- Department of Orthopaedics, Duke University School of Medicine, Durham, North Carolina, USA
| | - C Rory Goodwin
- Department of Neurosurgery, Duke University School of Medicine, Durham, North Carolina, USA
- Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, USA
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15
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Chintalacheruvu LM, Chilluru VK. Clinical Implications of Skin Cancer in Kidney Transplant Recipients in the Era of Immune Checkpoint Inhibitors. J Clin Med Res 2024; 16:571-577. [PMID: 39759492 PMCID: PMC11699868 DOI: 10.14740/jocmr6088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 12/02/2024] [Indexed: 01/07/2025] Open
Abstract
Long-term survival has improved in kidney transplant recipients (KTRs) due to effective surgical techniques and anti-rejection therapies. Chronic immunosuppression associated with it has led to several types of skin cancers leading to substantial morbidity and mortality. Structured patient education including sun protective behaviors, regular dermatological surveillance, nicotinamide, long-chain omega-3 polyunsaturated fatty acids (PUFAs), early switch to mammalian target of rapamycin inhibitors (mTORis), combining them with low-dose calcineurin inhibitors (CNIs), can decrease the cancer risk. Checkpoint inhibitors (CPIs) are the major backbone of the treatment of advanced skin cancers. Unfortunately, these agents can increase the risk of graft rejection. Prospective studies done so far looking at combining steroids with CPI in treatment of skin cancer in KTRs have shown mixed results. Adoption of the weight-based approach of CPI has shown to decrease the amount of drug exposure with acceptable outcomes in the general population, which is something that can be studied in KTRs with skin cancer. Also, it is reasonable to consider surveillance allograft biopsies in KTRs receiving CPIs to detect early subclinical rejection. More studies are needed to develop guidelines to safely treat this population with minimal graft rejection. We conducted a comprehensive literature review from PubMed on skin cancer in kidney transplant patients, focusing on incidence, risk factors, protective behaviors, financial and treatment implications, especially with regards to CPIs therapy. We also discussed potential newer treatment options that will decrease skin cancer risk, as well as graft rejection.
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Affiliation(s)
- Lakshmi Manogna Chintalacheruvu
- Hematology/Oncology, Southern Illinois Health Cancer Institute, Carterville, IL, USA
- Both authors contributed equally to this manuscript
| | - Vamsi Krishna Chilluru
- Nephrology, Southern Illinois Health, Carbondale, IL, USA
- Both authors contributed equally to this manuscript
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16
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Corica DA, Bell SD, Miller PJ, Kasperbauer DT, Lawler NJ, Wakefield MR, Fang Y. Into the Future: Fighting Melanoma with Immunity. Cancers (Basel) 2024; 16:4002. [PMID: 39682188 DOI: 10.3390/cancers16234002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 11/26/2024] [Accepted: 11/28/2024] [Indexed: 12/18/2024] Open
Abstract
Immunotherapy offers a novel and promising option in the treatment of late-stage melanoma. By utilizing the immune system to assist in tumor destruction, patients have additional options after tumor progression. Immune checkpoint inhibitors reduce the ability for tumors to evade the immune system by inhibiting key surface proteins used to inactivate T-cells. Without these surface proteins, T-cells can induce cytotoxic responses against tumors. Tumor infiltrating lymphocyte therapy is a form of adoptive cell therapy that takes advantage of a small subset of T-cells that recognize and infiltrate tumors. Isolation and rapid expansion of these colonies assist the immune system in mounting a charged response that can induce remission. Tumor vaccines deliver a high dose of unique antigens expressed by tumor cells to the entire body. The introduction of large quantities of tumor antigens upregulates antigen presenting cells and leads to effective activation of the immune system against tumors. Cytokine therapy introduces high amounts of chemical messengers that are endogenous to the immune system and support T-cell expansion. While other methods of immunotherapy exist, immune checkpoint inhibitors, tumor infiltrating lymphocytes, tumor vaccines, and cytokine therapy are commonly used to treat melanoma. Like many other cancer treatments, immunotherapy is not without adverse effects, as toxicities represent a major obstacle. However, immunotherapy has been efficacious in the treatment of melanoma.
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Affiliation(s)
- Derek A Corica
- Department of Microbiology, Immunology & Pathology, Des Moines University, West Des Moines, IA 50266, USA
| | - Scott D Bell
- Department of Microbiology, Immunology & Pathology, Des Moines University, West Des Moines, IA 50266, USA
| | - Peyton J Miller
- Department of Microbiology, Immunology & Pathology, Des Moines University, West Des Moines, IA 50266, USA
| | - Daniel T Kasperbauer
- Department of Microbiology, Immunology & Pathology, Des Moines University, West Des Moines, IA 50266, USA
| | - Nicholas J Lawler
- Department of Microbiology, Immunology & Pathology, Des Moines University, West Des Moines, IA 50266, USA
| | - Mark R Wakefield
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO 65212, USA
- Ellis Fischel Cancer Center, University of Missouri School of Medicine, Columbia, MO 65212, USA
| | - Yujiang Fang
- Department of Microbiology, Immunology & Pathology, Des Moines University, West Des Moines, IA 50266, USA
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO 65212, USA
- Ellis Fischel Cancer Center, University of Missouri School of Medicine, Columbia, MO 65212, USA
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17
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Zhang Y, Xie A, Wang D, Deng W. Novel Prognostic Markers for Skin Cutaneous Melanoma. Clin Cosmet Investig Dermatol 2024; 17:2615-2625. [PMID: 39588228 PMCID: PMC11586483 DOI: 10.2147/ccid.s486679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 11/15/2024] [Indexed: 11/27/2024]
Abstract
Background Skin cutaneous melanoma (SKCM) ranks among the most prevalent malignant tumors, highlighting the significance of identifying new research targets. In this study, our objective was to pinpoint pivotal genes implicated in SKCM pathogenesis and ascertain their potential as prognostic biomarkers. Methods Leveraging data from 1809 normal skin samples and 471 SKCM samples, we identified differentially expressed genes (DEGs). Using a comprehensive suite of bioinformatic analyses, including weighted gene co-expression network analysis (WGCNA), we elucidated the functions of these DEGs and singled out hub genes. Cox analyses and overall survival analyses underscored that elevated expression of these genes correlated with more favorable prognoses. Results Ultimately, we identified five genes (PLAC8, IL4I1, ZNF80, CCR8, CLEC4C) as novel prognostic markers for SKCM. Furthermore, multivariate Cox analyses pinpointed ZNF80 and CCR8 as independent prognostic biomarkers. Experimental validation targeting these genes revealed significant downregulation in melanoma cells, except for CCR8. Subsequent knockdown of IL4I1 promoted both the proliferation and inhibited the apoptosis of melanoma cells. Conclusion In summary, our study identified a series of potential prognostic genes in melanoma and verified the functional role of IL4I1 among them.
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Affiliation(s)
- Yi Zhang
- Department of Dermatology, the Affiliated Hospital of Inner Mongolia Medical University, Hohhot, People’s Republic of China
| | - Ansheng Xie
- Dermatology Hospital of Southern Medical University, Zhou Guang, People’s Republic of China
| | - Di Wang
- Dermatology Hospital of Southern Medical University, Zhou Guang, People’s Republic of China
| | - Weiwei Deng
- Dermatology Hospital of Southern Medical University, Zhou Guang, People’s Republic of China
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18
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Seyedi S, Harris VK, Kapsetaki SE, Narayanan S, Saha D, Compton Z, Yousefi R, May A, Fakir E, Boddy AM, Gerlinger M, Wu C, Mina L, Huijben S, Gouge DH, Cisneros L, Ellsworth PC, Maley CC. Resistance Management for Cancer: Lessons from Farmers. Cancer Res 2024; 84:3715-3727. [PMID: 39356625 PMCID: PMC11565176 DOI: 10.1158/0008-5472.can-23-3374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Revised: 06/29/2024] [Accepted: 09/23/2024] [Indexed: 10/04/2024]
Abstract
One of the main reasons we have not been able to cure cancers is that treatments select for drug-resistant cells. Pest managers face similar challenges with pesticides selecting for pesticide-resistant insects, resulting in similar mechanisms of resistance. Pest managers have developed 10 principles that could be translated to controlling cancers: (i) prevent onset, (ii) monitor continuously, (iii) identify thresholds below which there will be no intervention, (iv) change interventions in response to burden, (v) preferentially select nonchemical control methods, (vi) use target-specific drugs, (vii) use the lowest effective dose, (viii) reduce cross-resistance, (ix) evaluate success based on long-term management, and (x) forecast growth and response. These principles are general to all cancers and cancer drugs and so could be employed broadly to improve oncology. Here, we review the parallel difficulties in controlling drug resistance in pests and cancer cells. We show how the principles of resistance management in pests might be applied to cancer. Integrated pest management inspired the development of adaptive therapy in oncology to increase progression-free survival and quality of life in patients with cancers where cures are unlikely. These pest management principles have the potential to inform clinical trial design.
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Affiliation(s)
- Sareh Seyedi
- Arizona Cancer Evolution Center, Arizona State University, Tempe, Arizona
- Center for Biocomputing, Security and Society, Biodesign Institute, Arizona State University, Tempe, Arizona
- School of Life Sciences, Arizona State University, Tempe, Arizona
| | - Valerie K. Harris
- Arizona Cancer Evolution Center, Arizona State University, Tempe, Arizona
- Center for Biocomputing, Security and Society, Biodesign Institute, Arizona State University, Tempe, Arizona
| | - Stefania E. Kapsetaki
- Arizona Cancer Evolution Center, Arizona State University, Tempe, Arizona
- Center for Biocomputing, Security and Society, Biodesign Institute, Arizona State University, Tempe, Arizona
| | - Shrinath Narayanan
- Center for Biocomputing, Security and Society, Biodesign Institute, Arizona State University, Tempe, Arizona
- Department of Ecology and Evolution, University of Lausanne, Lausanne, Switzerland
| | - Daniel Saha
- Arizona Cancer Evolution Center, Arizona State University, Tempe, Arizona
- Center for Biocomputing, Security and Society, Biodesign Institute, Arizona State University, Tempe, Arizona
- School of Life Sciences, Arizona State University, Tempe, Arizona
| | - Zachary Compton
- Arizona Cancer Evolution Center, Arizona State University, Tempe, Arizona
- Center for Biocomputing, Security and Society, Biodesign Institute, Arizona State University, Tempe, Arizona
- School of Life Sciences, Arizona State University, Tempe, Arizona
- University of Arizona Cancer Center, University of Arizona College of Medicine, Tucson, Arizona
| | - Rezvan Yousefi
- Arizona Cancer Evolution Center, Arizona State University, Tempe, Arizona
- Center for Biocomputing, Security and Society, Biodesign Institute, Arizona State University, Tempe, Arizona
- The Polytechnic School, Ira A. Fulton Schools of Engineering, Arizona State University, Tempe, Arizona
| | - Alexander May
- Research Casting International, Quinte West, Ontario, Canada
| | - Efe Fakir
- Istanbul University Cerrahpasa School of Medicine, Istanbul, Turkey
| | - Amy M. Boddy
- Arizona Cancer Evolution Center, Arizona State University, Tempe, Arizona
- Exotic Species Cancer Research Alliance, North Carolina State University, Raleigh, North Carolina
- Department of Anthropology, University of California Santa Barbara, Santa Barbara, California
| | - Marco Gerlinger
- Translational Oncogenomics Laboratory, Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom
- Gastrointestinal Cancer Unit, The Royal Marsden Hospital, London, United Kingdom
| | - Christina Wu
- Division of Hematology and Medical Oncology, Department of Medicine, Mayo Clinic, Phoenix, Arizona
| | | | - Silvie Huijben
- School of Life Sciences, Arizona State University, Tempe, Arizona
- Center for Evolution and Medicine, Arizona State University, Tempe, Arizona
| | - Dawn H. Gouge
- Department of Entomology, University of Arizona, Tucson, Arizona
| | - Luis Cisneros
- Arizona Cancer Evolution Center, Arizona State University, Tempe, Arizona
- Center for Biocomputing, Security and Society, Biodesign Institute, Arizona State University, Tempe, Arizona
- School of Life Sciences, Arizona State University, Tempe, Arizona
| | | | - Carlo C. Maley
- Arizona Cancer Evolution Center, Arizona State University, Tempe, Arizona
- Center for Biocomputing, Security and Society, Biodesign Institute, Arizona State University, Tempe, Arizona
- School of Life Sciences, Arizona State University, Tempe, Arizona
- Center for Evolution and Medicine, Arizona State University, Tempe, Arizona
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19
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Cohen G, Rapoport B, Chan SW, Ruff P, Arance A, Mujika Eizmendi K, Houghton B, Brown MP, Zielinski RM, Muñoz Couselo E, Lyle M, Anderson JR, Jain L, de Alwis D, Lala M, Akala O, Chartash E, Jacobs C. Pembrolizumab 400 mg every 6 weeks as first-line therapy for advanced melanoma (KEYNOTE-555): Results from cohort B of an open-label, phase 1 study. PLoS One 2024; 19:e0309778. [PMID: 39531423 PMCID: PMC11556718 DOI: 10.1371/journal.pone.0309778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 07/02/2024] [Indexed: 11/16/2024] Open
Abstract
Intravenous pembrolizumab 400 mg every 6 weeks was approved across tumor types based on pharmacokinetic modeling, which showed exposures consistent with previous standard dosing of 200 mg or 2 mg/kg every 3 weeks, and early results of cohort B of the phase 1 KEYNOTE-555 study. Results after ≥1 year of potential follow-up for all patients in cohort B of KEYNOTE-555 are presented. Patients aged ≥18 years with previously untreated stage III/IV melanoma received pembrolizumab 400 mg every 6 weeks for ≤18 cycles. The primary endpoint was objective response rate per RECIST v1.1 by blinded independent central review. Secondary endpoints included duration of response, progression-free survival, pharmacokinetics, and safety. Overall, 101 patients received pembrolizumab. Median projected follow-up was 21.9 months (range, 17.0-25.7). The objective response rate was 50.5% (95% CI: 40.4-60.6; 19 complete responses, 32 partial responses). Median duration of response was not reached (NR; range, 2.4+ to 21.0+ months). Median progression-free survival was 13.8 months (95% CI: 4.1-NR). Observed pharmacokinetic exposures were consistent with model predictions for pembrolizumab 400 mg every 6 weeks and other approved and tested schedules (2 mg/kg or 200 mg every 3 weeks). Grade 3-4 treatment-related adverse events occurred in 13 patients (12.9%). No deaths were considered treatment related. These results support the pharmacokinetic modeling and demonstrate that the benefit-risk profile of pembrolizumab 400 mg Q6W is consistent with that of 200 mg or 2 mg/kg every 3 weeks. Clinically meaningful objective response rate and durable progression-free survival within the expected range for first-line pembrolizumab were observed. Clinical trial registry: ClinicalTrials.gov, NCT03665597.
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MESH Headings
- Humans
- Antibodies, Monoclonal, Humanized/administration & dosage
- Antibodies, Monoclonal, Humanized/pharmacokinetics
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antibodies, Monoclonal, Humanized/adverse effects
- Melanoma/drug therapy
- Melanoma/pathology
- Melanoma/mortality
- Middle Aged
- Female
- Male
- Aged
- Adult
- Antineoplastic Agents, Immunological/administration & dosage
- Antineoplastic Agents, Immunological/pharmacokinetics
- Antineoplastic Agents, Immunological/therapeutic use
- Antineoplastic Agents, Immunological/adverse effects
- Aged, 80 and over
- Progression-Free Survival
- Cohort Studies
- Drug Administration Schedule
- Treatment Outcome
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Affiliation(s)
- Graham Cohen
- Mary Potter Oncology Centre, Pretoria, South Africa
| | - Bernardo Rapoport
- The Medical Oncology Centre of Rosebank, Johannesburg, South Africa
- Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa
| | - Sze W. Chan
- Sandton Oncology, Johannesburg, South Africa
| | - Paul Ruff
- University of Witwatersrand Faculty of Health Sciences, Johannesburg, South Africa
| | - Ana Arance
- Hospital Clínic de Barcelona, Barcelona, Spain
| | | | - Baerin Houghton
- Port Macquarie Base Hospital, Port Macquarie, New South Wales, Australia
| | - Michael P. Brown
- Cancer Clinical Trials Unit, Royal Adelaide Hospital, and School of Medicine, The University of Adelaide, Adelaide, South Australia, Australia
| | - Robert M. Zielinski
- Central West Cancer Care Centre, Orange Hospital, Orange, New South Wales, Australia
- Western Sydney University, Sydney, New South Wales, Australia
| | - Eva Muñoz Couselo
- Department of Medical Oncology, Melanoma and Other Skin Cancers Unit, Vall d’Hebron University Hospital, Barcelona, Spain
| | - Megan Lyle
- Liz Plummer Cancer Care Centre, Cairns, Queensland, Australia
| | | | - Lokesh Jain
- Merck & Co., Inc., Rahway, New Jersey, United States of America
| | - Dinesh de Alwis
- Merck & Co., Inc., Rahway, New Jersey, United States of America
| | - Mallika Lala
- Merck & Co., Inc., Rahway, New Jersey, United States of America
| | - Omobolaji Akala
- Merck & Co., Inc., Rahway, New Jersey, United States of America
| | - Elliot Chartash
- Merck & Co., Inc., Rahway, New Jersey, United States of America
| | - Conrad Jacobs
- Cancer Care: Clinical & Radiation Oncology, Cape Town, South Africa
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20
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de Freitas JT, Thakur V, LaPorte KM, Thakur VS, Flores B, Caicedo V, Ajaegbu CGE, Ingrasci G, Lipman ZM, Zhang K, Qiu H, Malek TR, Bedogni B. Notch1 blockade by a novel, selective anti-Notch1 neutralizing antibody improves immunotherapy efficacy in melanoma by promoting an inflamed TME. J Exp Clin Cancer Res 2024; 43:295. [PMID: 39491031 PMCID: PMC11533310 DOI: 10.1186/s13046-024-03214-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 10/14/2024] [Indexed: 11/05/2024] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICI) have dramatically improved the life expectancy of patients with metastatic melanoma. However, about half of the patient population still present resistance to these treatments. We have previously shown Notch1 contributes to a non-inflamed TME in melanoma that reduces the response to ICI. Here, we addressed the therapeutic effects of a novel anti-Notch1 neutralizing antibody we produced, alone and in combination with immune checkpoint inhibition in melanoma models. METHODS Anti-Notch1 was designed to interfere with ligand binding. Mice were immunized with a peptide encompassing EGF-like repeats 11-15 of human Notch1, the minimal required region that allows ligand binding and Notch1 activation. Positive clones were expanded and tested for neutralizing capabilities. Anti-Notch1-NIC was used to determine whether anti-Notch1 was able to reduce Notch1 cleavage; while anti-SNAP23 and BCAT2 were used as downstream Notch1 and Notch2 targets, respectively. K457 human melanoma cells and the YUMM2.1 and 1.7 syngeneic mouse melanoma cells were used. Cell death after anti-Notch1 treatment was determined by trypan blue staining and compared to the effects of the gamma-secretase inhibitor DBZ. 10 mg/kg anti-Notch1 was used for in vivo tumor growth of YUMM2.1 and 1.7 cells. Tumors were measured and processed for flow cytometry using antibodies against major immune cell populations. RESULTS Anti-Notch1 selectively inhibited Notch1 but not Notch2; caused significant melanoma cell death in vitro but did not affect normal melanocytes. In vivo, it delayed tumor growth without evident signs of gastro-intestinal toxicities; and importantly promoted an inflamed TME by increasing the cytotoxic CD8+ T cells while reducing the tolerogenic Tregs and MDSCs, resulting in enhanced efficacy of anti-PD-1. CONCLUSIONS Anti-Notch1 safely exerts anti-melanoma effects and improves immune checkpoint inhibitor efficacy. Thus, anti-Notch1 could represent a novel addition to the immunotherapy repertoire for melanoma.
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Affiliation(s)
- Juliano Tiburcio de Freitas
- Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, 1600 NW 10th Ave, Miami, FL, 33136, USA
| | - Varsha Thakur
- Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, 1600 NW 10th Ave, Miami, FL, 33136, USA
| | - Kathryn M LaPorte
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, FL, 33136, USA
| | - Vijay S Thakur
- Department of Radiation Oncology, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, FL, 33136, USA
| | - Brian Flores
- Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, 1600 NW 10th Ave, Miami, FL, 33136, USA
| | - Valentina Caicedo
- Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, 1600 NW 10th Ave, Miami, FL, 33136, USA
| | - Chioma G E Ajaegbu
- Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, 1600 NW 10th Ave, Miami, FL, 33136, USA
| | - Giuseppe Ingrasci
- Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, 1600 NW 10th Ave, Miami, FL, 33136, USA
| | - Zoe M Lipman
- Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, 1600 NW 10th Ave, Miami, FL, 33136, USA
| | - Keman Zhang
- Department of Biochemistry, Case Western Reserve University, Cleveland, OH, 44106, USA
| | - Hong Qiu
- Department of Biochemistry, Case Western Reserve University, Cleveland, OH, 44106, USA
| | - Thomas R Malek
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, FL, 33136, USA
| | - Barbara Bedogni
- Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, 1600 NW 10th Ave, Miami, FL, 33136, USA.
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21
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Khan M, Dong Y, Ullah R, Li M, Huang Q, Hu Y, Yang L, Luo Z. Recent Advances in Bacterium-Based Therapeutic Modalities for Melanoma Treatment. Adv Healthc Mater 2024; 13:e2401076. [PMID: 39375965 DOI: 10.1002/adhm.202401076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 07/16/2024] [Indexed: 10/09/2024]
Abstract
Melanoma is one of the most severe skin cancer indications with rapid progression and a high risk of metastasis. However, despite the accumulated advances in melanoma treatment including adjuvant radiation, chemotherapy, and immunotherapy, the overall melanoma treatment efficacy in the clinics is still not satisfactory. Interestingly, bacterial therapeutics have demonstrated unique properties for tumor-related therapeutic applications, such as tumor-targeted motility, tailorable cytotoxicity, and immunomodulatory capacity of the tumor microenvironment, which have emerged as a promising platform for melanoma therapy. Indeed, the recent advances in genetic engineering and nanotechnologies have boosted the application potential of bacterium-based therapeutics for treating melanoma by further enhancing their tumor-homing, cell-killing, drug delivery, and immunostimulatory capacities. This review provides a comprehensive summary of the state-of-the-art bacterium-based anti-melanoma modalities, which are categorized according to their unique functional merits, including tumor-specific cytotoxins, tumor-targeted drug delivery platforms, and immune-stimulatory agents. Furthermore, a perspective is provided discussing the potential challenges and breakthroughs in this area. The insights in this review may facilitate the development of more advanced bacterium-based therapeutic modalities for improved melanoma treatment efficacy.
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Affiliation(s)
- Mubassir Khan
- Key Laboratory of Biorheological Science and Technology Ministry of Education College of Bioengineering Chongqing University Chongqing, Chongqing, 400044, P. R. China
| | - Yilong Dong
- Ruian People's Hospital, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325016, P. R. China
| | - Razi Ullah
- Key Laboratory for Biorheological Science and Technology of Ministry of Education, State and Local Joint Engineering Lab for Vascular Implants College of Bioengineering Chongqing University, Chongqing, 400030, P. R. China
| | - Menghuan Li
- School of Life Science, Chongqing University, Chongqing, 400044, P. R. China
| | - Qiping Huang
- Key Laboratory of Biorheological Science and Technology Ministry of Education College of Bioengineering Chongqing University Chongqing, Chongqing, 400044, P. R. China
| | - Yan Hu
- Key Laboratory of Biorheological Science and Technology Ministry of Education College of Bioengineering Chongqing University Chongqing, Chongqing, 400044, P. R. China
| | - Li Yang
- Key Laboratory of Biorheological Science and Technology Ministry of Education College of Bioengineering Chongqing University Chongqing, Chongqing, 400044, P. R. China
| | - Zhong Luo
- School of Life Science, Chongqing University, Chongqing, 400044, P. R. China
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22
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Koh YW, Han JH, Haam S, Lee HW. Impact of senescence cell signature in patients with non-small cell carcinoma and melanoma receiving PD-L1/PD-1 inhibitors. Mech Ageing Dev 2024; 222:111999. [PMID: 39427851 DOI: 10.1016/j.mad.2024.111999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 10/03/2024] [Accepted: 10/15/2024] [Indexed: 10/22/2024]
Abstract
Tumor cell senescence plays a crucial role in tumor immunity. We investigated whether the senescent cell signature (SCS) could predict prognosis in non-small cell carcinoma (NSCLC) and melanoma datasets treated with PD-L1/PD-1 inhibitors. Patients with high SCS expression exhibited elevated levels of interferon-gamma and T cell-inflamed signatures in three lung adenocarcinomas (LUAD), two squamous cell carcinoma (LUSC) and three melanoma datasets. The high SCS group was associated with PD-L1-related pathways such as IL6/JAK/STAT3 and TNF-alpha signaling via NF-kB in LUAD, LUSC, and melanoma datasets. A positive correlation was observed between several immune checkpoint markers and the SCS, indicating an immunosuppressive state in LUAD, LUSC and melanoma datasets. In patients treated with PD-1/PD-L1 inhibitors, a higher SCS was associated with a better prognosis, and a positive correlation between SCS and PD-L1 was observed in six independent NSCLC and three independent melanoma datasets. We used the LASSO Cox regression model to build a risk model focusing on the SCS genes that particularly predict prognosis. We confirmed that the model accurately predicts prognosis. However, the senescent immunohistochemical markers p16 and p21 could predict the response to PD-1/PD-L1 inhibitors in patients with LUSC and melanoma but not in patients with LUAD. SCS could serve as a valuable biomarker to complement PD-L1 expression in patients receiving PD-L1/PD-1 inhibitors.
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Affiliation(s)
- Young Wha Koh
- Department of Pathology, Ajou University School of Medicine, Suwon-si, South Korea.
| | - Jae-Ho Han
- Department of Pathology, Ajou University School of Medicine, Suwon-si, South Korea
| | - Seokjin Haam
- Department of Thoracic and Cardiovascular Surgery, Ajou University School of Medicine, Suwon-si, South Korea
| | - Hyun Woo Lee
- Department of Hematology-Oncology, Ajou University School of Medicine, Suwon-si, South Korea
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23
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Schroeder C, Gatidis S, Kelemen O, Schütz L, Bonzheim I, Muyas F, Martus P, Admard J, Armeanu-Ebinger S, Gückel B, Küstner T, Garbe C, Flatz L, Pfannenberg C, Ossowski S, Forschner A. Tumour-informed liquid biopsies to monitor advanced melanoma patients under immune checkpoint inhibition. Nat Commun 2024; 15:8750. [PMID: 39384805 PMCID: PMC11464631 DOI: 10.1038/s41467-024-52923-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Accepted: 09/20/2024] [Indexed: 10/11/2024] Open
Abstract
Immune checkpoint inhibitors (ICI) have significantly improved overall survival in melanoma patients. However, 60% experience severe adverse events and early response markers are lacking. Circulating tumour DNA (ctDNA) is a promising biomarker for treatment-response and recurrence detection. The prospective PET/LIT study included 104 patients with palliative combined or adjuvant ICI. Tumour-informed sequencing panels to monitor 30 patient-specific variants were designed and 321 liquid biopsies of 87 patients sequenced. Mean sequencing depth after deduplication using UMIs was 6000x and the error rate of UMI-corrected reads was 2.47×10-4. Variant allele fractions correlated with PET/CT MTV (rho=0.69), S100 (rho=0.72), and LDH (rho=0.54). A decrease of allele fractions between T1 and T2 was associated with improved PFS and OS in the palliative cohort (p = 0.008 and p < 0.001). ctDNA was detected in 76.9% of adjuvant patients with relapse (n = 10/13), while all patients without progression (n = 9) remained ctDNA negative. Tumour-informed liquid biopsies are a reliable tool for monitoring treatment response and early relapse in melanoma patients with ICI.
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Affiliation(s)
- Christopher Schroeder
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
- German Cancer Consortium (DKTK), partner site Tübingen, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Sergios Gatidis
- Department of Radiology, Diagnostic and Interventional Radiology, University Hospital Tübingen, Tübingen, Germany
| | - Olga Kelemen
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
| | - Leon Schütz
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
| | - Irina Bonzheim
- Institute of Pathology and Neuropathology, University Hospital Tübingen, Tübingen, Germany
| | - Francesc Muyas
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
| | - Peter Martus
- Institute for Clinical Epidemiology and Applied Biostatistics (IKEaB), Tübingen, Germany
| | - Jakob Admard
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
- NGS Competence Center Tübingen (NCCT), University of Tübingen, Tübingen, Germany
| | - Sorin Armeanu-Ebinger
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
| | - Brigitte Gückel
- Department of Radiology, Diagnostic and Interventional Radiology, University Hospital Tübingen, Tübingen, Germany
| | - Thomas Küstner
- Department of Radiology, Diagnostic and Interventional Radiology, University Hospital Tübingen, Tübingen, Germany
| | - Claus Garbe
- Department of Dermatology, University Hospital Tübingen, Tübingen, Germany
| | - Lukas Flatz
- Department of Dermatology, University Hospital Tübingen, Tübingen, Germany
| | - Christina Pfannenberg
- Department of Radiology, Diagnostic and Interventional Radiology, University Hospital Tübingen, Tübingen, Germany
| | - Stephan Ossowski
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
- German Cancer Consortium (DKTK), partner site Tübingen, German Cancer Research Center (DKFZ), Heidelberg, Germany
- NGS Competence Center Tübingen (NCCT), University of Tübingen, Tübingen, Germany
- Institute for Bioinformatics and Medical Informatics (IBMI), University of Tübingen, Tübingen, Germany
| | - Andrea Forschner
- Department of Dermatology, University Hospital Tübingen, Tübingen, Germany.
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24
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Wu Z, Sun W, Wang C. Clinical characteristics, treatment, and outcomes of pembrolizumab-induced uveitis. Invest New Drugs 2024; 42:510-517. [PMID: 39141261 DOI: 10.1007/s10637-024-01464-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Accepted: 08/12/2024] [Indexed: 08/15/2024]
Abstract
Pembrolizumab has been associated with episodes of uveitis, and the clinical characteristics between them are unknown. The aim of this study was to investigate the clinical characteristics of pembrolizumab-induced uveitis and to provide reference for prevention, diagnosis and treatment. We collected studies related to pembrolizumab-induced uveitis by searching databases for retrospective analysis until April 30, 2024. The median age of the 31 patients was 63 years (range 7, 82), and the median duration of uveitis onset was 12 weeks (range 0.4, 108). Decreased vision (41.9%) and blurred vision (25.8%) were the most common complaints. Uveitis can be manifested as Vogt-Koyanagi-Harada disease-like uveitis (22.6%) and Birdshot uveitis (6.5%). Uveitis mainly affects both eyes and is related to anterior uveitis (35.5%), panuveitis (25.8%) and posterior uveitis (19.4%). Patients receiving topical steroid drops, systemic steroids, and withdrawal of pembrolizumab significantly improved symptoms at a median time of 4 weeks (range 2, 16). The possibility of uveitis should be considered when patients are treated with pembrolizumab and experience eye symptoms such as blurred vision and decreased vision. Depending on the severity of uveitis, treatment with topical and systemic steroids may be selected.
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Affiliation(s)
- Zhaoquan Wu
- College of pharmacy, Changsha Medical University, No. 1501 Leifeng Avenue, Xiangjiang New District, Changsha, Hunan, 410219, China
- Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha, Hunan, 410219, China
| | - Wei Sun
- Department of pharmacy, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China
| | - Chunjiang Wang
- College of pharmacy, Changsha Medical University, No. 1501 Leifeng Avenue, Xiangjiang New District, Changsha, Hunan, 410219, China.
- Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha, Hunan, 410219, China.
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25
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Zhao X, Zhao Z, Li B, Huan S, Li Z, Xie J, Liu G. ACSL4-mediated lipid rafts prevent membrane rupture and inhibit immunogenic cell death in melanoma. Cell Death Dis 2024; 15:695. [PMID: 39343834 PMCID: PMC11439949 DOI: 10.1038/s41419-024-07098-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 09/17/2024] [Accepted: 09/20/2024] [Indexed: 10/01/2024]
Abstract
Chemotherapy including platinum-based drugs are a possible strategy to enhance the immune response in advanced melanoma patients who are resistant to immune checkpoint blockade (ICB) therapy. However, the immune-boosting effects of these drugs are a subject of controversy, and their impact on the tumor microenvironment are poorly understood. In this study, we discovered that lipid peroxidation (LPO) promotes the formation of lipid rafts in the membrane, which mediated by Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4) impairs the sensitivity of melanoma cells to platinum-based drugs. This reduction primarily occurs through the inhibition of immunogenic ferroptosis and pyroptosis by reducing cell membrane pore formation. By disrupting ACSL4-mediaged lipid rafts via the removal of membrane cholesterol, we promoted immunogenic cell death, transformed the immunosuppressive environment, and improved the antitumor effectiveness of platinum-based drugs and immune response. This disruption also helped reverse the decrease in CD8+ T cells while maintaining their ability to secrete cytokines. Our results reveal that ACSL4-dependent LPO is a key regulator of lipid rafts formation and antitumor immunity, and that disrupting lipid rafts has the potential to enhance platinum-based drug-induced immunogenic ferroptosis and pyroptosis in melanoma. This novel strategy may augment the antitumor immunity of platinum-based therapy and further complement ICB therapy.
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Affiliation(s)
- Xi Zhao
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
- Department of Pharmaceutical Analysis, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Zenglu Zhao
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
- Department of Pharmaceutical Analysis, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Bingru Li
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
- Department of Pharmaceutical Analysis, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Shuyu Huan
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
- Department of Pharmaceutical Analysis, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Zixi Li
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
- Department of Pharmaceutical Analysis, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Jianlan Xie
- Department of Pathology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Guoquan Liu
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China.
- Department of Pharmaceutical Analysis, School of Pharmaceutical Sciences, Peking University, Beijing, China.
- Department of Biomedical Engineering, Institute of Advanced Clinical Medicine, Peking University, Beijing, 100191, China.
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26
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Chen YC, Zheng WZ, Liu CP, Zhao YQ, Li JW, Du ZS, Zhai TT, Lin HY, Shi WQ, Cai SQ, Pan F, Qiu SQ. Pan-cancer analysis reveals CCL5/CSF2 as potential predictive biomarkers for immune checkpoint inhibitors. Cancer Cell Int 2024; 24:311. [PMID: 39256838 PMCID: PMC11389493 DOI: 10.1186/s12935-024-03496-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 08/31/2024] [Indexed: 09/12/2024] Open
Abstract
BACKGROUND Currently, there are no optimal biomarkers available for distinguishing patients who will respond to immune checkpoint inhibitors (ICIs) therapies. Consequently, the exploration of novel biomarkers that can predict responsiveness to ICIs is crucial in the field of immunotherapy. METHODS We estimated the proportions of 22 immune cell components in 10 cancer types (6,128 tumors) using the CIBERSORT algorithm, and further classified patients based on their tumor immune cell proportions in a pan-cancer setting using k-means clustering. Differentially expressed immune genes between the patient subgroups were identified, and potential predictive biomarkers for ICIs were explored. Finally, the predictive value of the identified biomarkers was verified in patients with urothelial carcinoma (UC) and esophageal squamous cell carcinoma (ESCC) who received ICIs. RESULTS Our study identified two subgroups of patients with distinct immune infiltrating phenotypes and differing clinical outcomes. The patient subgroup with improved outcomes displayed tumors enriched with genes related to immune response regulation and pathway activation. Furthermore, CCL5 and CSF2 were identified as immune-related hub-genes and were found to be prognostic in a pan-cancer setting. Importantly, UC and ESCC patients with high expression of CCL5 and low expression of CSF2 responded better to ICIs. CONCLUSION We demonstrated CCL5 and CSF2 as potential novel biomarkers for predicting the response to ICIs in patients with UC and ESCC. The predictive value of these biomarkers in other cancer types warrants further evaluation in future studies.
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Affiliation(s)
- Yi-Chao Chen
- Clinical Research Center, Shantou Central Hospital, Shantou, 515041, China
| | - Wei-Zhong Zheng
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, 999077, China
| | - Chun-Peng Liu
- Department of Pathology, Shantou Central Hospital, Shantou, 515041, China
| | - Yong-Qiang Zhao
- Department of Pathology, Shantou Central Hospital, Shantou, 515041, China
| | - Jun-Wei Li
- Clinical Research Center, Shantou Central Hospital, Shantou, 515041, China
| | - Ze-Sen Du
- Surgical Oncology Department, Shantou Central Hospital, Shantou, 515041, China
| | - Tian-Tian Zhai
- Radiation Oncology Department, The Cancer Hospital of Shantou University Medical College, Shantou, 515041, China
| | - Hao-Yu Lin
- Department of Thyroid and Breast Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, China
| | - Wen-Qi Shi
- Clinical Research Center, Shantou Central Hospital, Shantou, 515041, China
| | - Shan-Qing Cai
- Department of Pathology, Shantou Central Hospital, Shantou, 515041, China
| | - Feng Pan
- Clinical Research Center, Shantou Central Hospital, Shantou, 515041, China.
| | - Si-Qi Qiu
- Clinical Research Center, Shantou Central Hospital, Shantou, 515041, China.
- Diagnosis and Treatment Center of Breast Diseases, Shantou Central Hospital, Shantou, 515041, China.
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27
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Bullock AJ, Schlechter BL, Fakih MG, Tsimberidou AM, Grossman JE, Gordon MS, Wilky BA, Pimentel A, Mahadevan D, Balmanoukian AS, Sanborn RE, Schwartz GK, Abou-Alfa GK, Segal NH, Bockorny B, Moser JC, Sharma S, Patel JM, Wu W, Chand D, Rosenthal K, Mednick G, Delepine C, Curiel TJ, Stebbing J, Lenz HJ, O'Day SJ, El-Khoueiry AB. Botensilimab plus balstilimab in relapsed/refractory microsatellite stable metastatic colorectal cancer: a phase 1 trial. Nat Med 2024; 30:2558-2567. [PMID: 38871975 PMCID: PMC11405281 DOI: 10.1038/s41591-024-03083-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Accepted: 05/22/2024] [Indexed: 06/15/2024]
Abstract
Microsatellite stable metastatic colorectal cancer (MSS mCRC; mismatch repair proficient) has previously responded poorly to immune checkpoint blockade. Botensilimab (BOT) is an Fc-enhanced multifunctional anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody designed to expand therapy to cold/poorly immunogenic solid tumors, such as MSS mCRC. BOT with or without balstilimab (BAL; anti-PD-1 antibody) is being evaluated in an ongoing expanded phase 1 study. The primary endpoint is safety and tolerability, which was evaluated separately in the dose-escalation portion of the study and in patients with MSS mCRC (using combined dose-escalation/dose-expansion data). Secondary endpoints include investigator-assessed RECIST version 1.1-confirmed objective response rate (ORR), disease control rate (DCR), duration of response (DOR) and progression-free survival (PFS). Here we present outcomes in 148 heavily pre-treated patients with MSS mCRC (six from the dose-escalation cohort; 142 from the dose-expansion cohort) treated with BOT and BAL, 101 of whom were considered response evaluable with at least 6 months of follow-up. Treatment-related adverse events (TRAEs) occurred in 89% of patients with MSS mCRC (131/148), most commonly fatigue (35%, 52/148), diarrhea (32%, 47/148) and pyrexia (24%, 36/148), with no grade 5 TRAEs reported and a 12% discontinuation rate due to a TRAE (18/148; data fully mature). In the response-evaluable population (n = 101), ORR was 17% (17/101; 95% confidence interval (CI), 10-26%), and DCR was 61% (62/101; 95% CI, 51-71%). Median DOR was not reached (NR; 95% CI, 5.7 months-NR), and median PFS was 3.5 months (95% CI, 2.7-4.1 months), at a median follow-up of 10.3 months (range, 0.5-42.6 months; data continuing to mature). The combination of BOT plus BAL demonstrated a manageable safety profile with no new immune-mediated safety signals and encouraging clinical activity with durable responses. ClinicalTrials.gov identifier: NCT03860272 .
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MESH Headings
- Humans
- Colorectal Neoplasms/drug therapy
- Colorectal Neoplasms/genetics
- Colorectal Neoplasms/pathology
- Female
- Male
- Middle Aged
- Aged
- Adult
- Antibodies, Monoclonal, Humanized/adverse effects
- Antibodies, Monoclonal, Humanized/administration & dosage
- Antibodies, Monoclonal, Humanized/therapeutic use
- Aged, 80 and over
- Microsatellite Instability/drug effects
- Neoplasm Metastasis
- Microsatellite Repeats/genetics
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Antineoplastic Combined Chemotherapy Protocols/adverse effects
- Neoplasm Recurrence, Local/drug therapy
- Neoplasm Recurrence, Local/pathology
- Neoplasm Recurrence, Local/genetics
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Affiliation(s)
| | | | - Marwan G Fakih
- City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | | | | | | | | | - Agustin Pimentel
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA
| | - Daruka Mahadevan
- The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | | | - Rachel E Sanborn
- Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, USA
| | - Gary K Schwartz
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA
| | - Ghassan K Abou-Alfa
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Medical College at Cornell University, New York, NY, USA
- Trinity College Dublin, Dublin, Ireland
| | - Neil H Segal
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Medical College at Cornell University, New York, NY, USA
| | | | | | - Sunil Sharma
- HonorHealth Research Institute, Scottsdale, AZ, USA
| | | | - Wei Wu
- Agenus, Inc., Lexington, MA, USA
| | | | | | | | | | | | | | - Heinz-Josef Lenz
- University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA
| | - Steven J O'Day
- Agenus, Inc., Lexington, MA, USA
- Providence Saint John's Cancer Institute, Santa Monica, CA, USA
| | - Anthony B El-Khoueiry
- University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
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Qu C, Shao X, Jia R, Song G, Shi D, Wang H, Wang J, An H. Hypoxia Reversion and STING Pathway Activation through Large Mesoporous Nanozyme for Near-Infrared-II Light Amplified Tumor Polymetallic-Immunotherapy. ACS NANO 2024; 18:22153-22171. [PMID: 39118372 DOI: 10.1021/acsnano.4c05483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/10/2024]
Abstract
cGAS/STING pathway, which is highly related to tumor hypoxia, is considered as a potential target for remodeling the immunosuppressive microenvironment of solid tumors. Metal ions, such as Mn2+, activate the cGAS/STING pathway, but their efficacy in cancer therapy is limited by insufficient effect on immunogenic tumor cell death of a single ion. Here, we evaluate the association between tumor hypoxia and cGAS/STING inhibition and report a polymetallic-immunotherapy strategy based on large mesoporous trimetal-based nanozyme (AuPdRh) coordinated with Mn2+ (Mn2+@AuPdRh) to activate cGAS/STING signaling for robust adaptive antitumor immunity. Specifically, the inherent CAT-like activity of this polymetallic Mn2+@AuPdRh nanozyme decomposes the endogenous H2O2 into O2 to relieve tumor hypoxia induced suppression of cGAS/STING signaling. Moreover, the Mn2+@AuPdRh nanozyme displays a potent near-infrared-II photothermal effect and strong POD-mimic activity; and the generated hyperthermia and •OH radicals synergistically trigger immunogenic cell death in tumors, releasing abundant dsDNA, while the delivered Mn2+ augments the sensitivity of cGAS to dsDNA and activates the cGAS-STING pathway, thereby triggering downstream immunostimulatory signals to kill primary and distant metastatic tumors. Our study demonstrates the potential of metal-based nanozyme for STING-mediated tumor polymetallic-immunotherapy and may inspire the development of more effective strategies for cancer immunotherapy.
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Affiliation(s)
- Chang Qu
- Key Laboratory of Molecular Biophysics of Hebei Province, Institute of Biophysics, School of Health Sciences and Biomedical Engineering, Hebei University of Technology, 300401, Tianjin, People's Republic of China
- State Key Laboratory of Reliability and Intelligence of Electrical Equipment, School of Electrical Engineering, Hebei University of Technology, 300130, Tianjin, People's Republic of China
| | - Xinyue Shao
- Key Laboratory of Molecular Biophysics of Hebei Province, Institute of Biophysics, School of Health Sciences and Biomedical Engineering, Hebei University of Technology, 300401, Tianjin, People's Republic of China
| | - Ran Jia
- Key Laboratory of Molecular Biophysics of Hebei Province, Institute of Biophysics, School of Sciences, Hebei University of Technology, 300401, Tianjin, People's Republic of China
| | - Guoqiang Song
- Key Laboratory of Molecular Biophysics of Hebei Province, Institute of Biophysics, School of Health Sciences and Biomedical Engineering, Hebei University of Technology, 300401, Tianjin, People's Republic of China
| | - Donghong Shi
- Key Laboratory of Molecular Biophysics of Hebei Province, Institute of Biophysics, School of Health Sciences and Biomedical Engineering, Hebei University of Technology, 300401, Tianjin, People's Republic of China
| | - Hui Wang
- Key Laboratory of Molecular Biophysics of Hebei Province, Institute of Biophysics, School of Health Sciences and Biomedical Engineering, Hebei University of Technology, 300401, Tianjin, People's Republic of China
| | - Jinping Wang
- Key Laboratory of Molecular Biophysics of Hebei Province, Institute of Biophysics, School of Health Sciences and Biomedical Engineering, Hebei University of Technology, 300401, Tianjin, People's Republic of China
| | - Hailong An
- Key Laboratory of Molecular Biophysics of Hebei Province, Institute of Biophysics, School of Health Sciences and Biomedical Engineering, Hebei University of Technology, 300401, Tianjin, People's Republic of China
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29
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Jiang W, Cheng Y, Hou L, Huang Y, Wang S, Zhang Y, Jiang T, Yang F, Ma Z. A dual-prodrug nanogel combining Vorinostat and Pyropheophorbide a for a high efficient photochemotherapy. Int J Pharm 2024; 661:124422. [PMID: 38977163 DOI: 10.1016/j.ijpharm.2024.124422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 06/17/2024] [Accepted: 07/03/2024] [Indexed: 07/10/2024]
Abstract
The challenges posed by intractable relapse and metastasis in cancer treatment have led to the development of various forms of photodynamic therapy (PDT). However, traditional drug delivery systems, such as virus vectors, liposomes, and polymers, often suffer from issues like desynchronized drug release, carrier instability, and drug leakage during circulation. To address these problems, we have developed a dual-prodrug nanogel (PVBN) consisting of Pyro (Pyropheophorbide a) and SAHA (Vorinostat) bound to BSA (Bovine Serum Albumin), which facilitates synchronous and spontaneous drug release in situ within the lysosome. Detailed results indicate that PVBN-treated tumor cells exhibit elevated levels of ROS and Acetyl-H3, leading to necrosis, apoptosis, and cell cycle arrest, with PDT playing a dominant role in the synergistic therapeutic effect. Furthermore, the anti-tumor efficacy of PVBN was validated in melanoma-bearing mice, where it significantly inhibited tumor growth and pulmonary metastasis. Overall, our dual-prodrug nanogel, formed by the binding of SAHA and Pyro to BSA and releasing drugs within the lysosome, represents a novel and promising strategy for enhancing the clinical efficacy of photochemotherapy.
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Affiliation(s)
- Weiwei Jiang
- School of Pharmacy, Naval Medical University, Shanghai, China
| | - Yuwei Cheng
- Department of Pharmacy, Hebei North University Hebei Key Laboratory of Neuropharmacology, Zhangjiakou, China
| | - Lei Hou
- Department of Pharmacy, Hebei North University Hebei Key Laboratory of Neuropharmacology, Zhangjiakou, China
| | - Ying Huang
- Department of Pharmacy, Hebei North University Hebei Key Laboratory of Neuropharmacology, Zhangjiakou, China
| | - Sizhen Wang
- School of Pharmacy, Naval Medical University, Shanghai, China
| | - Yunchang Zhang
- School of Pharmacy, Naval Medical University, Shanghai, China
| | - Tao Jiang
- Department of Nuclear Medicine, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
| | - Feng Yang
- School of Pharmacy, Naval Medical University, Shanghai, China; Department of Nuclear Medicine, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
| | - Zhiqiang Ma
- School of Pharmacy, Naval Medical University, Shanghai, China.
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30
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Gao B, Wang Y, Zhang X, Jiang H, Han F, Li C, Lu S. Identification and validation of inflammatory subtypes in intrahepatic cholangiocellular carcinoma. J Transl Med 2024; 22:730. [PMID: 39103879 DOI: 10.1186/s12967-024-05529-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 07/23/2024] [Indexed: 08/07/2024] Open
Abstract
BACKGROUND Inflammation plays a critical role in tumor development. Inflammatory cell infiltration and inflammatory mediator synthesis cause changes in the tumor microenvironment (TME) in several cancers, especially in intrahepatic cholangiocellular carcinoma (ICC). However, methods to ascertain the inflammatory state of patients using reliable biomarkers are still being explored. METHOD We retrieved the RNA sequencing and somatic mutation analyses results and the clinical characteristics of 244 patients with ICC from published studies. We performed consensus clustering to identify the molecular subtypes associated with inflammation. We compared the prognostic patterns, clinical characteristics, somatic mutation profiles, and immune cell infiltration patterns across inflammatory subtypes. We performed quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) to confirm gene expression. We performed logistic regression analyses to construct a nomogram predicting the inflammatory status of patients with ICC. RESULTS Our results confirmed that ICC can be categorized into an inflammation-high subtype (IHS) and an inflammation-low subtype (ILS). Patients from each group had distinct prognosis, clinical characteristics, and TME composition. Patients with ICC in the IHS group showed poorer prognosis owing to the immunosuppressive microenvironment and high frequency of KRAS and TP53 mutations. Cancer-associated fibroblast (CAF)-derived COLEC11 reduced myeloid inflammatory cell infiltration and attenuated inflammatory responses. The results of qRT-PCR and IHC experiments confirmed that COLEC11 expression levels were significantly reduced in tumor tissues compared to those in paracancerous tissues. Patients with ICC in the IHS group were more likely to respond to treatment with immune checkpoint inhibitors (ICIs) owing to their higher tumor mutational burden (TMB) scores, tumor neoantigen burden (TNB) scores, neoantigen counts, and immune checkpoint expression levels. Finally, we developed a nomogram to effectively predict the inflammatory status of patients with ICC based on their clinical characteristics and inflammatory gene expression levels. We evaluated the calibration, discrimination potential, and clinical utility of the nomogram. CONCLUSION The inflammatory response in IHS is primarily induced by myeloid cells. COLEC11 can reduce the infiltration level of this group of cells, and myeloid inflammatory cells may be a novel target for ICC treatment. We developed a novel nomogram that could effectively predict the inflammatory state of patients with ICC, which will be useful for guiding individualized treatment plans.
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Affiliation(s)
- Biao Gao
- Nankai University School of Medicine, Nankai University, Tianjin, China
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital, Beijing, China
- Institute of Hepatobiliary Surgery of Chinese PLA, Beijing, China
- Key Laboratory of Digital Hepatobiliary Surgery of Chinese PLA, Beijing, China
| | - Yafei Wang
- Nankai University School of Medicine, Nankai University, Tianjin, China
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital, Beijing, China
- Institute of Hepatobiliary Surgery of Chinese PLA, Beijing, China
- Key Laboratory of Digital Hepatobiliary Surgery of Chinese PLA, Beijing, China
| | - Xianzhou Zhang
- Department of Hepatic Biliary Pancreatic Surgery, Cancer Hospital, Zhengzhou University, Zhengzhou, 450000, Henan Province, China
| | - Hao Jiang
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital, Beijing, China
- Institute of Hepatobiliary Surgery of Chinese PLA, Beijing, China
- Key Laboratory of Digital Hepatobiliary Surgery of Chinese PLA, Beijing, China
| | - Feng Han
- Department of Hepatic Biliary Pancreatic Surgery, Cancer Hospital, Zhengzhou University, Zhengzhou, 450000, Henan Province, China.
| | - Chonghui Li
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital, Beijing, China.
- Institute of Hepatobiliary Surgery of Chinese PLA, Beijing, China.
- Key Laboratory of Digital Hepatobiliary Surgery of Chinese PLA, Beijing, China.
| | - Shichun Lu
- Nankai University School of Medicine, Nankai University, Tianjin, China.
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital, Beijing, China.
- Institute of Hepatobiliary Surgery of Chinese PLA, Beijing, China.
- Key Laboratory of Digital Hepatobiliary Surgery of Chinese PLA, Beijing, China.
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31
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Zager JS, Hyams DM. Management of melanoma: can we use gene expression profiling to help guide treatment and surveillance? Clin Exp Metastasis 2024; 41:439-445. [PMID: 38064126 DOI: 10.1007/s10585-023-10241-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 11/03/2023] [Indexed: 09/05/2024]
Abstract
Although the incidence of cutaneous melanoma (CM) has been increasing annually, the mortality rate has been decreasing, likely due to better prevention, earlier detection, improved surveillance, and the development of new therapies. Current clinical management guidelines by the National Comprehensive Cancer Network (NCCN) are based on patient risk assignment using staging criteria established by the American Joint Committee on Cancer (AJCC). However, some patients with localized disease (stage I-II), generally considered to have a good prognosis, will develop metastatic disease and die, whereas some patients with later stage disease (stage III-IV) will be cured by surgery, adjuvant therapy, and/or systemic therapy. These results emphasize the importance of identifying patients whose risk may be over or underestimated with standard staging. Gene expression profile (GEP) tests are noninvasive molecular tests that assess the expression levels of a panel of validated genes, providing information about tumor prognosis, including the risk of recurrence, metastasis, and cancer-specific death. GEP tests can provide prognostic information beyond standard staging that may aid clinicians and patients in treatment and surveillance management decisions. This review describes how combining clinicopathologic staging with a robust assessment of tumor biology may provide information that will allow more refined intervention and long-term management.
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Affiliation(s)
- Jonathan S Zager
- Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL, USA.
- Department of Oncologic Sciences, University of South Florida Morsani College of Medicine, 10920 McKinley Dr., Tampa, FL, 33612, USA.
| | - David M Hyams
- Desert Surgical Oncology, Eisenhower Medical Center, Rancho Mirage, CA, USA
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32
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Zhang C, Wang H, Aji T, Li Z, Li Y, Ainiwaer A, Rousu Z, Li J, Wang M, Deng B, Duolikun A, Kang X, Zheng X, Yu Q, Shao Y, Zhang W, Vuitton DA, Tian Z, Sun H, Wen H. Targeting myeloid-derived suppressor cells promotes antiparasitic T-cell immunity and enhances the efficacy of PD-1 blockade (15 words). Nat Commun 2024; 15:6345. [PMID: 39068159 PMCID: PMC11283557 DOI: 10.1038/s41467-024-50754-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 07/18/2024] [Indexed: 07/30/2024] Open
Abstract
Immune exhaustion corresponds to a loss of effector function of T cells that associates with cancer or chronic infection. Here, our objective was to decipher the mechanisms involved in the immune suppression of myeloid-derived suppressor cells (MDSCs) and to explore the potential to target these cells for immunotherapy to enhance checkpoint blockade efficacy in a chronic parasite infection. We demonstrated that programmed cell-death-1 (PD-1) expression was significantly upregulated and associated with T-cell dysfunction in advanced alveolar echinococcosis (AE) patients and in Echinococcus multilocularis-infected mice. PD-1 blockade ex vivo failed to reverse AE patients' peripheral blood T-cell dysfunction. PD-1/PD-L1 blockade or PD-1 deficiency had no significant effects on metacestode in mouse model. This was due to the inhibitory capacities of immunosuppressive granulocytic MDSCs (G-MDSCs), especially in the liver surrounding the parasite pseudotumor. MDSCs suppressed T-cell function in vitro in an indoleamine 2, 3 dioxygenase 1 (IDO1)-dependent manner. Although depleting MDSCs alone restored T-cell effector functions and led to some limitation of disease progression in E. multilocularis-infected mice, combination with PD-1 blockade was better to induce antiparasitic efficacy. Our findings provide preclinical evidence in support of targeting MDSC or combining such an approach with checkpoint blockade in patients with advanced AE. (200 words).
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Affiliation(s)
- Chuanshan Zhang
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University; Clinical Medicine Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, P. R. China.
- Basic Medical College, Xinjiang Medical University, Urumqi, Xinjiang, P. R. China.
- Key Laboratory of High Incidence Disease Research in Xingjiang, Ministry of Education, Xinjiang Medical University, Urumqi, Xinjiang, P. R. China.
| | - Hui Wang
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University; Clinical Medicine Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, P. R. China
- Key Laboratory of High Incidence Disease Research in Xingjiang, Ministry of Education, Xinjiang Medical University, Urumqi, Xinjiang, P. R. China
- Xinjiang Key Laboratory of Echinococcosis, Clinical Medicine Research Institute, The First Affiliated Hospital of Xinjiang Medical University, and WHO Collaborating Centre on Prevention and Case Management of Echinococcosis, Urumqi, Xinjiang, P. R. China
| | - Tuerganaili Aji
- Key Laboratory of High Incidence Disease Research in Xingjiang, Ministry of Education, Xinjiang Medical University, Urumqi, Xinjiang, P. R. China
- Department of Hepatic Hydatid and Hepatobiliary Surgery, Digestive and Vascular Surgery Centre, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, P. R. China
| | - Zhide Li
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University; Clinical Medicine Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, P. R. China
| | - Yinshi Li
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University; Clinical Medicine Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, P. R. China
- Basic Medical College, Xinjiang Medical University, Urumqi, Xinjiang, P. R. China
| | - Abidan Ainiwaer
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University; Clinical Medicine Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, P. R. China
- Basic Medical College, Xinjiang Medical University, Urumqi, Xinjiang, P. R. China
| | - Zibigu Rousu
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University; Clinical Medicine Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, P. R. China
- Basic Medical College, Xinjiang Medical University, Urumqi, Xinjiang, P. R. China
| | - Jing Li
- Basic Medical College, Xinjiang Medical University, Urumqi, Xinjiang, P. R. China
| | - Maolin Wang
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University; Clinical Medicine Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, P. R. China
- Department of Hepatic Hydatid and Hepatobiliary Surgery, Digestive and Vascular Surgery Centre, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, P. R. China
| | - Bingqing Deng
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University; Clinical Medicine Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, P. R. China
- Basic Medical College, Xinjiang Medical University, Urumqi, Xinjiang, P. R. China
| | - Adilai Duolikun
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University; Clinical Medicine Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, P. R. China
- Basic Medical College, Xinjiang Medical University, Urumqi, Xinjiang, P. R. China
| | - Xuejiao Kang
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University; Clinical Medicine Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, P. R. China
- Basic Medical College, Xinjiang Medical University, Urumqi, Xinjiang, P. R. China
| | - Xuran Zheng
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University; Clinical Medicine Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, P. R. China
- Basic Medical College, Xinjiang Medical University, Urumqi, Xinjiang, P. R. China
| | - Qian Yu
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University; Clinical Medicine Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, P. R. China
- Basic Medical College, Xinjiang Medical University, Urumqi, Xinjiang, P. R. China
| | - Yingmei Shao
- Department of Hepatic Hydatid and Hepatobiliary Surgery, Digestive and Vascular Surgery Centre, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, P. R. China
| | - Wenbao Zhang
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University; Clinical Medicine Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, P. R. China
- Xinjiang Key Laboratory of Echinococcosis, Clinical Medicine Research Institute, The First Affiliated Hospital of Xinjiang Medical University, and WHO Collaborating Centre on Prevention and Case Management of Echinococcosis, Urumqi, Xinjiang, P. R. China
| | - Dominique A Vuitton
- WHO-Collaborating Centre for the Prevention and Treatment of Human Echinococcosis, Department of Parasitology, University Bourgogne Franche-Comté (EA 3181) and University Hospital, Besançon, France
| | - Zhigang Tian
- Hefei National Research Center for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, P. R. China
| | - Haoyu Sun
- Hefei National Research Center for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, P. R. China.
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
- Institute of Immunology, University of Science and Technology of China, Hefei, Anhui, P. R. China.
| | - Hao Wen
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University; Clinical Medicine Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, P. R. China.
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33
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Mitchell TC. Valuable insights from the epacadostat plus pembrolizumab clinical trials in solid cancers. BMC Cancer 2024; 23:1269. [PMID: 39054487 PMCID: PMC11270756 DOI: 10.1186/s12885-024-12432-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/27/2024] Open
Affiliation(s)
- Tara C Mitchell
- Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
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34
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Axelrad JE, Hashash JG, Itzkowitz SH. AGA Clinical Practice Update on Management of Inflammatory Bowel Disease in Patients With Malignancy: Commentary. Clin Gastroenterol Hepatol 2024; 22:1365-1372. [PMID: 38752967 DOI: 10.1016/j.cgh.2024.03.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 03/16/2024] [Accepted: 03/25/2024] [Indexed: 06/23/2024]
Abstract
DESCRIPTION The purpose of this American Gastroenterological Association (AGA) Institute Clinical Practice Update (CPU) Commentary is to discuss the risks of various malignancies in patients with inflammatory bowel diseases (IBD) and the impact of the available medical therapies on these risks. The CPU will also guide the approach to the patient with IBD who develops a malignancy or the patient with a history of cancer in terms of IBD medication management. METHODS This CPU was commissioned and approved by the AGA Institute CPU committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership and underwent internal peer review by the CPU committee and external peer review through standard procedures of Clinical Gastroenterology and Hepatology. This communication incorporates important and recently published studies in the field, and it reflects the experiences of the authors who are experts in the diagnosis and management of IBD.
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Affiliation(s)
- Jordan E Axelrad
- Inflammatory Bowel Disease Center at NYU Langone Health, Division of Gastroenterology, NYU Grossman School of Medicine, New York, New York.
| | - Jana G Hashash
- Inflammatory Bowel Disease Center, Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida
| | - Steven H Itzkowitz
- Division of Gastroenterology, the Icahn School of Medicine at Mount Sinai, New York, New York
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Glitza IC, Seo YD, Spencer CN, Wortman JR, Burton EM, Alayli FA, Loo CP, Gautam S, Damania A, Densmore J, Fairchild J, Cabanski CR, Wong MC, Peterson CB, Weiner B, Hicks N, Aunins J, McChalicher C, Walsh E, Tetzlaff MT, Hamid O, Ott PA, Boland GM, Sullivan RJ, Grossmann KF, Ajami NJ, LaVallee T, Henn MR, Tawbi HA, Wargo JA. Randomized Placebo-Controlled, Biomarker-Stratified Phase Ib Microbiome Modulation in Melanoma: Impact of Antibiotic Preconditioning on Microbiome and Immunity. Cancer Discov 2024; 14:1161-1175. [PMID: 38588588 PMCID: PMC11215408 DOI: 10.1158/2159-8290.cd-24-0066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 03/01/2024] [Accepted: 03/12/2024] [Indexed: 04/10/2024]
Abstract
Gut-microbiota modulation shows promise in improving immune-checkpoint blockade (ICB) response; however, precision biomarker-driven, placebo-controlled trials are lacking. We performed a multicenter, randomized placebo-controlled, biomarker-stratified phase I trial in patients with ICB-naïve metastatic melanoma using SER-401, an orally delivered Firmicutesenriched spore formulation. Fecal microbiota signatures were characterized at baseline; patients were stratified by high versus low Ruminococcaceae abundance prior to randomization to the SER-401 arm (oral vancomycin-preconditioning/SER-401 alone/nivolumab + SER-401), versus the placebo arm [placebo antibiotic/placebo microbiome modulation (PMM)/nivolumab + PMM (NCT03817125)]. Analysis of 14 accrued patients demonstrated that treatment with SER-401 + nivolumab was safe, with an overall response rate of 25% in the SER-401 arm and 67% in the placebo arm (though the study was underpowered related to poor accrual during the COVID-19 pandemic). Translational analyses demonstrated that vancomycin preconditioning was associated with the disruption of the gut microbiota and impaired immunity, with incomplete recovery at ICB administration (particularly in patients with high baseline Ruminococcaceae). These results have important implications for future microbiome modulation trials. Significance: This first-of-its-kind, placebo-controlled, randomized biomarker-driven microbiome modulation trial demonstrated that vancomycin + SER-401 and anti-PD-1 are safe in melanoma patients. Although limited by poor accrual during the pandemic, important insights were gained via translational analyses, suggesting that antibiotic preconditioning and interventional drug dosing regimens should be carefully considered when designing such trials.
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Affiliation(s)
- Isabella C. Glitza
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
| | - Yongwoo David Seo
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
| | | | | | - Elizabeth M. Burton
- Strategic Translational Research Initiative Development, The University of Texas MD Anderson Cancer Center, Houston, Texas.
| | - Farah A. Alayli
- Parker Institute for Cancer Immunotherapy, San Francisco, California.
| | | | - Shikha Gautam
- Parker Institute for Cancer Immunotherapy, San Francisco, California.
| | - Ashish Damania
- Platform for Innovative Microbiome and Translational Research, Moon Shots Program, The University of Texas MD Anderson Cancer Center, Houston, Texas.
| | - Julie Densmore
- Parker Institute for Cancer Immunotherapy, San Francisco, California.
| | - Justin Fairchild
- Parker Institute for Cancer Immunotherapy, San Francisco, California.
- Portage Biotech, Westport, Connecticut.
| | | | - Matthew C. Wong
- Platform for Innovative Microbiome and Translational Research, Moon Shots Program, The University of Texas MD Anderson Cancer Center, Houston, Texas.
| | - Christine B. Peterson
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
| | | | | | - John Aunins
- Seres Therapeutics, Cambridge, Massachusetts.
| | | | - Emily Walsh
- Seres Therapeutics, Cambridge, Massachusetts.
| | - Michael T. Tetzlaff
- Department of Pathology, University of California San Francisco, San Francisco, California.
| | - Omid Hamid
- Cutaneous Oncology, The Angeles Clinic and Research Institute, A Cedars-Sinai Affiliate, Los Angeles, California.
| | - Patrick A. Ott
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts.
| | - Genevieve M. Boland
- Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
| | - Ryan J. Sullivan
- Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
| | | | - Nadim J. Ajami
- Platform for Innovative Microbiome and Translational Research, Moon Shots Program, The University of Texas MD Anderson Cancer Center, Houston, Texas.
| | - Theresa LaVallee
- Parker Institute for Cancer Immunotherapy, San Francisco, California.
- Coherus BioSciences, Redwood City, California.
| | | | - Hussein A. Tawbi
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
| | - Jennifer A. Wargo
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Castanares-Zapatero D, Verleye L, Devos C, Thiry N, Silversmit G, Van Damme N, De Gendt C, Hulstaert F, Neyt M. Survival of patients with unfavorable prognosis cutaneous melanoma with increased use of immunotherapy agents: a population-based study in Belgium. Int J Dermatol 2024; 63:947-955. [PMID: 38297428 DOI: 10.1111/ijd.17046] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 01/05/2024] [Accepted: 01/09/2024] [Indexed: 02/02/2024]
Abstract
BACKGROUND Although metastatic cutaneous melanoma is associated with an unfavorable prognosis, innovative therapies including immunomodulating agents and targeted therapies have shown survival benefits in clinical trials. We assessed the impact of the introduction of innovative drugs into clinical practice on the survival of patients with metastatic cutaneous melanoma during the period 2004-2017, in Belgium. The evolution of associated expenses was also analyzed. METHODS This is a retrospective population-based study using data from the national Belgian Cancer Registry, compulsory health insurance, and administrative survival data. The immunomodulating drugs were ipilimumab, nivolumab and pembrolizumab, while targeted therapies included vemurafenib, dabrafenib and trametinib. RESULTS We did not identify a trend for improvement over time. Median survival (years) was 1.5 (95% CI: 1.1-1.8) in 2004-2008, 1.1 (95% CI: 0.8-1.5) in 2009-2013, and 1.6 (95% CI: 1.3-2.4) in 2014-2017, respectively. In contrast, survival improved in those with unknown primary tumor localization. In this group, median survival time was 2.0 (95% CI: 1.4-2.9) in the most recent period, while it was 1.1 (95% CI: 0.7-1.3) in 2009-2013, and 0.9 (95% CI: 0.6-1.2) in 2004-2008. The uptake of innovative drugs remained modest, with no drug being used by more than 30% of patients. Yearly expenditure was almost non-existent, and gradually increased, reaching several million euros in 2014-2017. CONCLUSION Patients with metastatic cutaneous melanoma who were diagnosed between 2004 and 2017 showed no apparent improvement in survival. In contrast, increased survival was observed in the subgroup of patients with unknown primary tumor localization.
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Affiliation(s)
| | - Leen Verleye
- Belgian Health Care Knowledge Centre (KCE), Brussels, Belgium
| | - Carl Devos
- Belgian Health Care Knowledge Centre (KCE), Brussels, Belgium
| | - Nancy Thiry
- Belgian Health Care Knowledge Centre (KCE), Brussels, Belgium
| | | | | | | | - Frank Hulstaert
- Belgian Health Care Knowledge Centre (KCE), Brussels, Belgium
| | - Mattias Neyt
- Belgian Health Care Knowledge Centre (KCE), Brussels, Belgium
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Quandt Z, Jacob S, Fadlullah MZH, Wu C, Wu C, Huppert L, Levine LS, Sison P, Tsai KK, Chow M, Kang JH, Hwang J, Lee JC, Oglesby A, Venegas J, Brintz BJ, Tan AC, Anderson MS, Rosenblum MD, Young A, Daud AI. Phase II trial of pembrolizumab, ipilimumab, and aspirin in melanoma: clinical outcomes and translational predictors of response. BJC REPORTS 2024; 2:46. [PMID: 39516257 PMCID: PMC11524064 DOI: 10.1038/s44276-024-00057-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 02/26/2024] [Accepted: 03/08/2024] [Indexed: 11/16/2024]
Abstract
OBJECTIVE Many patients with melanoma treated with immune checkpoint inhibitors (ICIs) do not derive response. Preclinical and retrospective studies identified that inhibition of the cyclooxygenase (COX) pathway may improve response to ICI treatment. METHODS This prospective single site phase II trial accrued patients with advanced/metastatic melanoma. Participants underwent high-dose aspirin daily combined with pembrolizumab and ipilimumab every 3 weeks for 4 cycles followed by high-dose aspirin and pembrolizumab monotherapy. The primary endpoint was objective response rate (ORR). Longitudinal sampling of blood was performed to assess peripheral immune correlates. RESULTS Twenty-seven subjects were enrolled with median follow-up of 32 months. An ORR of 62.9% was reached prior to discontinuation due to low likelihood of achieving the pre-specified ORR of 80%. 17 patients (63%) experienced a treatment-related adverse event (TRAEs) grade 3 or higher. A per-protocol analysis showed that patients able to continue aspirin alongside ICI through the induction period experienced significant survival benefit. Ten cytokines and increased regulatory T cells in the periphery correlated with beneficial response. CONCLUSIONS The addition of high-dose aspirin to combination ICI within this study results in response comparable to ICI alone. Future clinical studies of COX inhibition will need to focus on mitigation of AEs to establish the clinical utility of this combination.
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Affiliation(s)
- Zoe Quandt
- Department of Medicine, University of California San Francisco, San Francisco, CA, 94143, USA
- Diabetes Center, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Saya Jacob
- Department of Medicine, University of California San Francisco, San Francisco, CA, 94143, USA
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94143, USA
| | | | - Chaorong Wu
- Division of Epidemiology, University of Utah, Salt Lake City, UT, 84112, USA
| | - Clinton Wu
- Department of Medicine, University of California San Francisco, San Francisco, CA, 94143, USA
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Laura Huppert
- Department of Medicine, University of California San Francisco, San Francisco, CA, 94143, USA
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Lauren S Levine
- Department of Medicine, University of California San Francisco, San Francisco, CA, 94143, USA
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Paula Sison
- Department of Medicine, University of California San Francisco, San Francisco, CA, 94143, USA
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Katy K Tsai
- Department of Medicine, University of California San Francisco, San Francisco, CA, 94143, USA
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Melissa Chow
- Department of Medicine, University of California San Francisco, San Francisco, CA, 94143, USA
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Jee Hye Kang
- Diabetes Center, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Jimmy Hwang
- Department of Medicine, University of California San Francisco, San Francisco, CA, 94143, USA
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94143, USA
| | - James C Lee
- Department of Medicine, University of California San Francisco, San Francisco, CA, 94143, USA
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Ariel Oglesby
- Department of Medicine, University of California San Francisco, San Francisco, CA, 94143, USA
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Jessica Venegas
- Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, UT, 84112, USA
- Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, 84112, USA
| | - Ben J Brintz
- Division of Epidemiology, University of Utah, Salt Lake City, UT, 84112, USA
| | - Aik Choon Tan
- Departments of Oncological Sciences and Biomedical Informatics, University of Utah, Salt Lake City, UT, 84112, USA
- Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, UT, 84112, USA
| | - Mark S Anderson
- Department of Medicine, University of California San Francisco, San Francisco, CA, 94143, USA
- Diabetes Center, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Michael D Rosenblum
- Dermatology, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Arabella Young
- Diabetes Center, University of California San Francisco, San Francisco, CA, 94143, USA.
- Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, UT, 84112, USA.
- Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, 84112, USA.
| | - Adil I Daud
- Department of Medicine, University of California San Francisco, San Francisco, CA, 94143, USA.
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94143, USA.
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Zhang X, Zheng P, Meng B, Zhuang H, Lu B, Yao J, Han F, Luo S. Histamine-related genes participate in the establishment of an immunosuppressive microenvironment and impact the immunotherapy response in hepatocellular carcinoma. Clin Exp Med 2024; 24:129. [PMID: 38884870 PMCID: PMC11182831 DOI: 10.1007/s10238-024-01399-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Accepted: 06/10/2024] [Indexed: 06/18/2024]
Abstract
Chronic inflammation is pivotal in the pathogenesis of hepatocellular carcinoma (HCC). Histamine is a biologically active substance that amplifies the inflammatory and immune response and serves as a neurotransmitter. However, knowledge of histamine's role in HCC and its effects on immunotherapy remains lacking. We focused on histamine-related genes to investigate their potential role in HCC. The RNA-seq data and clinical information regarding HCC were obtained from The Cancer Genome Atlas (TCGA). After identifying the differentially expressed genes, we constructed a signature using the univariate Cox proportional hazard regression and least absolute shrinkage and selection operator (LASSO) analyses. The signature's predictive performance was evaluated using a receiver operating characteristic curve (ROC) analysis. Furthermore, drug sensitivity, immunotherapy effects, and enrichment analyses were conducted. Histamine-related gene expression in HCC was confirmed using quantitative real-time polymerase chain reaction (qRT-PCR). A histamine-related gene prognostic signature (HRGPS) was developed in TCGA. Time-dependent ROC and Kaplan-Meier survival analyses demonstrated the signature's strong predictive power. Importantly, patients in high-risk groups exhibited a higher frequency of TP53 mutations, elevated immune checkpoint-related gene expression, and increased infiltration of immunosuppressive cells-indicating a potentially favorable response to immunotherapy. In addition, drug sensitivity analysis revealed that the signature could effectively predict chemotherapy efficacy and sensitivity. qRT-PCR results validated histamine-related gene overexpression in HCC. Our findings demonstrate that inhibiting histamine-related genes and signaling pathways can impact the therapeutic effect of anti-PD-1/PD-L1. The precise predictive ability of our signature in determining the response to different therapeutic options highlights its potential clinical significance.
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Affiliation(s)
- Xianzhou Zhang
- Department of Hepatic Biliary Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Peng Zheng
- Department of Hepatic Biliary Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Bo Meng
- Department of Hepatic Biliary Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Hao Zhuang
- Department of Hepatic Biliary Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Bing Lu
- Department of Hepatic Biliary Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Jun Yao
- Department of Hepatic Biliary Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Feng Han
- Department of Hepatic Biliary Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, 450008, China.
| | - Suxia Luo
- Department of Hepatic Biliary Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, 450008, China.
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Bidgood GM, Keating N, Doggett K, Nicholson SE. SOCS1 is a critical checkpoint in immune homeostasis, inflammation and tumor immunity. Front Immunol 2024; 15:1419951. [PMID: 38947335 PMCID: PMC11211259 DOI: 10.3389/fimmu.2024.1419951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Accepted: 05/28/2024] [Indexed: 07/02/2024] Open
Abstract
The Suppressor of Cytokine Signaling (SOCS) family proteins are important negative regulators of cytokine signaling. SOCS1 is the prototypical member of the SOCS family and functions in a classic negative-feedback loop to inhibit signaling in response to interferon, interleukin-12 and interleukin-2 family cytokines. These cytokines have a critical role in orchestrating our immune defence against viral pathogens and cancer. The ability of SOCS1 to limit cytokine signaling positions it as an important immune checkpoint, as evidenced by the detection of detrimental SOCS1 variants in patients with cytokine-driven inflammatory and autoimmune disease. SOCS1 has also emerged as a key checkpoint that restricts anti-tumor immunity, playing both a tumor intrinsic role and impacting the ability of various immune cells to mount an effective anti-tumor response. In this review, we describe the mechanism of SOCS1 action, focusing on the role of SOCS1 in autoimmunity and cancer, and discuss the potential for new SOCS1-directed cancer therapies that could be used to enhance adoptive immunotherapy and immune checkpoint blockade.
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Affiliation(s)
- Grace M. Bidgood
- Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
- Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia
| | - Narelle Keating
- Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
- Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia
| | - Karen Doggett
- Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
- Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia
| | - Sandra E. Nicholson
- Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
- Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia
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Wang Y, Ran T, Li Y, Tian L, Yang L, Liu Z, Yao B. Identification of JUN gene and cellular microenvironment in response to PD-1 blockade treatment in lung cancer patients via single-cell RNA sequencing. Aging (Albany NY) 2024; 16:10348-10365. [PMID: 38874497 PMCID: PMC11236306 DOI: 10.18632/aging.205932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 05/03/2024] [Indexed: 06/15/2024]
Abstract
Exploring the molecular mechanisms of PD-1/PDL-1 blockade for non-small cell lung cancer (NSCLC) would facilitate understanding for tumor microenvironment (TME) and development of individualized medicine. To date, biomarkers of response to PD-1 blockade therapy were still limited. In this study, we hypothesize that cell type in the tumor microenvironment can influence the effect of PD-1 blockade immunotherapy through specific genes. Therefore, we re-analyze the single-cell RNA sequencing data and validation in tissue from lung adenocarcinoma patients. Dynamic changes of cellular subpopulation were observed after anti-PD-1 immunotherapy among TMEs between primary/metastasis or good/poor response patients. Non-exhausted CD8 T cells and dysregulated genes were observed in responsing patients from PD-1 blockade therapy. Among all changed genes, JUN, involved in PD-1 blockade immunotherapy pathway, and could be considered as a PD-1 responsing biomarker.
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Affiliation(s)
- Yuxuan Wang
- No.2 Department of Thoracic Surgery, Beijing Tuberculosis and Thoracic Tumor Research Institute/Beijing Chest Hospital, Capital Medical University, Beijing, China
| | - Tao Ran
- Department of Oncology, Tongren People’s Hospital, Tongren, Guizhou, China
| | - Yunke Li
- Beijing Digitf Biotechnology Co., Ltd, Beijing, China
| | - Lei Tian
- Department of Oncology, Tongren People’s Hospital, Tongren, Guizhou, China
| | - Lifeng Yang
- Department of Oncology, Tongren People’s Hospital, Tongren, Guizhou, China
| | - Zhidong Liu
- No.2 Department of Thoracic Surgery, Beijing Tuberculosis and Thoracic Tumor Research Institute/Beijing Chest Hospital, Capital Medical University, Beijing, China
| | - Biao Yao
- Department of Oncology, Tongren People’s Hospital, Tongren, Guizhou, China
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Zhang N, Chang J, Liu P, Tian X, Yu J. Prognostic significance of programmed cell death ligand 1 blood markers in non-small cell lung cancer treated with immune checkpoint inhibitors: a systematic review and meta-analysis. Front Immunol 2024; 15:1400262. [PMID: 38915398 PMCID: PMC11194356 DOI: 10.3389/fimmu.2024.1400262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 05/29/2024] [Indexed: 06/26/2024] Open
Abstract
Background Immune checkpoint inhibitors (ICIs) are effective for non-small cell lung cancer (NSCLC) treatment, but the response rate remains low. Programmed cell death ligand 1 (PD-L1) in peripheral blood, including soluble form (sPD-L1), expression on circulating tumor cells (CTCs PD-L1) and exosomes (exoPD-L1), are minimally invasive and promising markers for patient selection and management, but their prognostic significance remains inconclusive. Here, we performed a meta-analysis for the prognostic value of PD-L1 blood markers in NSCLC patients treated with ICIs. Methods Eligible studies were obtained by searching PubMed, EMBAS, Web of Science, and Cochrane Library prior to November 30, 2023. The associations between pre-treatment, post-treatment and dynamic changes of blood PD-L1 levels and progression-free survival (PFS)/over survival (OS) were analyzed by estimating hazard ratio (HR) and 95% confidence interval (CI). Results A total of 26 studies comprising 1606 patients were included. High pre- or post-treatment sPD-L1 levels were significantly associated with worse PFS (pre-treatment: HR=1.49, 95%CI 1.13-1.95; post-treatment: HR=2.09, 95%CI 1.40-3.12) and OS (pre-treatment: HR=1.83, 95%CI 1.25-2.67; post-treatment: HR=2.60, 95%CI 1.09-6.20, P=0.032). High pre-treatment exoPD-L1 levels predicted a worse PFS (HR=4.24, 95%CI 2.82-6.38, P<0.001). Pre-treatment PD-L1+ CTCs tended to be correlated with prolonged PFS (HR=0.63, 95%CI 0.39-1.02) and OS (HR=0.58, 95%CI 0.36-0.93). Patients with up-regulated exoPD-L1 levels, but not sPD-L1, after ICIs treatment had significantly favorable PFS (HR=0.36, 95%CI 0.23-0.55) and OS (HR=0.24, 95%CI 0.08-0.68). Conclusion PD-L1 blood markers, including sPD-L1, CTCs PD-L1 and exoPD-L1, can effectively predict prognosis, and may be potentially utilized for patient selection and treatment management for NSCLC patients receiving ICIs.
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Affiliation(s)
| | | | | | | | - Junyan Yu
- Department of Oncology, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, China
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He C, Guo Y, Zhou N, Wang Z, Liu T, Xu X, Wang F, Zhu H, Yang Z, Yang X, Xia L. Construction and Application of a PD-L1-Targeted Multimodal Diagnostic and Dual-Functional Theranostics Nanoprobe. Int J Nanomedicine 2024; 19:5479-5492. [PMID: 38863646 PMCID: PMC11166151 DOI: 10.2147/ijn.s461701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Accepted: 05/29/2024] [Indexed: 06/13/2024] Open
Abstract
Background In recent years, PD-L1 has been primarily utilized as an immune checkpoint marker in cancer immunotherapy. However, due to tumor heterogeneity, the response rate to such therapies often falls short of expectations. In addition to its role in immunotherapy, PD-L1 serves as a specific target on the surface of tumor cells for targeted diagnostic and therapeutic interventions. There is an absence of a fully developed PD-L1-targeted diagnostic and therapeutic probe for clinical use, which constrains the exploration and clinical exploitation of this target. Methods and Results In this study, we engineered a PD-L1-targeted probe with multimodal imaging and dual therapeutic functionalities utilizing organic melanin nanoparticles. Functionalization with the WL12-SH peptide endowed the nanoprobe with specific targeting capabilities. Subsequent radiolabeling with 89Zr (half-life: 100.8 hours) and chelation of Mn2+ ions afforded the probe the capacity for simultaneous PET and MRI imaging modalities. Cellular uptake assays revealed pronounced specificity, with -positive cells exhibiting significantly higher uptake than -negative counterparts (p < 0.05). Dual-modal PET/MRI imaging delineated rapid and sustained accumulation at the neoplastic site, yielding tumor-to-non-tumor (T/NT) signal ratios at 24 hours post-injection of 16.67±3.45 for PET and 6.63±0.64 for MRI, respectively. We conjugated the therapeutic radionuclide 131I (half-life: 8.02 days) to the construct and combined low-dose radiotherapy and photothermal treatment (PTT), culminating in superior antitumor efficacy while preserving a high safety profile. The tumors in the cohort receiving the dual-modality therapy exhibited significantly reduced volume and weight compared to those in the control and monotherapy groups. Conclusion We developed and applied a novel -targeted multimodal theranostic nanoprobe, characterized by its high specificity and superior imaging capabilities as demonstrated in PET/MRI modalities. Furthermore, this nanoprobe facilitates potent therapeutic efficacy at lower radionuclide doses when used in conjunction with PTT.
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Affiliation(s)
- Chengxue He
- Medical College, Guizhou University, Guiyang, GuiZhou Province, People’s Republic of China
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China
| | - YanHui Guo
- Department of Radiology, Peking University Third Hospital, Beijing, People’s Republic of China
| | - Nina Zhou
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China
| | - Zhen Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Hepato-Pancreato-Biliary Surgery, Sarcoma Center, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China
| | - Teli Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China
| | - Xiaoxia Xu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China
| | - Feng Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China
| | - Hua Zhu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China
| | - Zhi Yang
- Medical College, Guizhou University, Guiyang, GuiZhou Province, People’s Republic of China
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China
| | - Xianteng Yang
- Medical College, Guizhou University, Guiyang, GuiZhou Province, People’s Republic of China
- Department of Orthopedics, Guizhou Provincial People’s Hospital, Guiyang, GuiZhou Province, People’s Republic of China
| | - Lei Xia
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China
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Cheng Z, Yang C, Zhao Q, Zhong J, Zhang J, Jin R, Li Y, Ta N, Wu D, Yuan Z, Sun W, Wang R. Efficacy and predictors of immune checkpoint inhibitors in patients with gallbladder cancer. Cancer Sci 2024; 115:1979-1988. [PMID: 38487949 PMCID: PMC11145113 DOI: 10.1111/cas.16142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 02/03/2024] [Accepted: 02/25/2024] [Indexed: 06/04/2024] Open
Abstract
Immune checkpoint inhibitors (ICIs) have shown promising efficacy in multiple cancers including biliary tract cancers (BTCs). However, the data focusing on the efficacy of ICIs in patients with gallbladder cancer (GBC) is still limited. In this study, we aim to assess the efficacy of ICIs in GBC and explore the clinicopathologic and molecular markers associated with ICI benefit. We retrospective analyzed 69 GBC patients who had received ICI therapy between January 2016 and December 2020. Tumor samples were obtained for genomic sequencing and immunohistochemical analysis. The median progression-free survival (PFS) and overall survival (OS) was 4.4 months and 8.5 months, respectively. Multivariate analysis indicated that alcohol intake history, carcinoma embryonic antigen (CEA) level ≥100 U/mL, and cutaneous immune-related adverse events (irAEs) were independent prognostic factors for PFS. CEA level ≥100 U/mL and cutaneous irAEs were independent prognostic factors for OS. The objective response rate and disease control rate (DCR) were 15.9% and 37.7%, respectively. Patients with cutaneous irAEs, high CD8+ T cell infiltrated or immune inflamed GBCs had higher DCR. Patients with high CD8+ T cell infiltrated or immune inflamed GBCs also had a notably improved prognosis. These results suggest that ICIs were effective in patients with GBC. High CEA level, cutaneous irAEs, high CD8+ T cell infiltration, and immune inflamed phenotype could be useful for predicting the efficacy of ICIs in GBC.
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Affiliation(s)
- Zhuo Cheng
- Department of Oncology, Eastern Hepatobiliary Surgery HospitalNaval Medical UniversityShanghaiChina
| | - Cheng Yang
- Department of Special Treatment I and Liver Transplantation, Eastern Hepatobiliary Surgery HospitalNaval Medical UniversityShanghaiChina
| | - Qian Zhao
- Department of PathologyShanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Jingjiao Zhong
- Department of RadiologyChanghai Hospital, Naval Medical UniversityShanghaiChina
| | - Jin Zhang
- The First Department of Hepatic Surgery, Eastern Hepatobiliary Surgery HospitalNaval Medical UniversityShanghaiChina
| | - Riming Jin
- The First Department of Hepatic Surgery, Eastern Hepatobiliary Surgery HospitalNaval Medical UniversityShanghaiChina
| | - Yao Li
- The First Department of Hepatic Surgery, Eastern Hepatobiliary Surgery HospitalNaval Medical UniversityShanghaiChina
| | - Na Ta
- Department of Pathology, Changhai HospitalNaval Medical UniversityShanghaiChina
| | - Dong Wu
- The First Department of Hepatic Surgery, Eastern Hepatobiliary Surgery HospitalNaval Medical UniversityShanghaiChina
| | - Zhengang Yuan
- Department of Oncology, Eastern Hepatobiliary Surgery HospitalNaval Medical UniversityShanghaiChina
| | - Wen Sun
- National Center for Liver CancerNaval Medical UniversityShanghaiChina
| | - Ruoyu Wang
- The First Department of Hepatic Surgery, Eastern Hepatobiliary Surgery HospitalNaval Medical UniversityShanghaiChina
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Monnickendam G. Assessing the Performance of Alternative Methods for Estimating Long-Term Survival Benefit of Immuno-oncology Therapies. VALUE IN HEALTH : THE JOURNAL OF THE INTERNATIONAL SOCIETY FOR PHARMACOECONOMICS AND OUTCOMES RESEARCH 2024; 27:746-754. [PMID: 38428815 DOI: 10.1016/j.jval.2024.02.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 02/18/2024] [Accepted: 02/22/2024] [Indexed: 03/03/2024]
Abstract
OBJECTIVES This study aimed to determine the accuracy and consistency of established methods of extrapolating mean survival for immuno-oncology (IO) therapies, the extent of any systematic biases in estimating long-term clinical benefit, what influences the magnitude of any bias, and the potential implications for health technology assessment. METHODS A targeted literature search was conducted to identify published long-term follow-up from clinical trials of immune-checkpoint inhibitors. Earlier published results were identified and Kaplan-Meier estimates for short- and long-term follow-up were digitized and converted to pseudo-individual patient data using an established algorithm. Six standard parametric, 5 flexible parametric, and 2 mixture-cure models (MCMs) were used to extrapolate long-term survival. Mean and restricted mean survival time (RMST) were estimated and compared between short- and long-term follow-up. RESULTS Predicted RMST from extrapolation of early data underestimated observed RMST in long-term follow-up for 184 of 271 extrapolations. All models except the MCMs frequently underestimated observed RMST. Mean survival estimates increased with longer follow-up in 196 of 270 extrapolations. The increase exceeded 20% in 122 extrapolations. Log-logistic and log-normal models showed the smallest change with additional follow-up. MCM performance varied substantially with functional form. CONCLUSIONS Standard and flexible parametric models frequently underestimate mean survival for IO treatments. Log-logistic and log-normal models may be the most pragmatic and parsimonious solutions for estimating IO mean survival from immature data. Flexible parametric models may be preferred when the data used in health technology assessment are more mature. MCMs fitted to immature data produce unreliable results and are not recommended.
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Gupta M, Stukalin I, Meyers DE, Heng DYC, Monzon J, Cheng T, Navani V. Imaging response to immune checkpoint inhibitors in patients with advanced melanoma: a retrospective observational cohort study. Front Oncol 2024; 14:1385425. [PMID: 38884085 PMCID: PMC11176500 DOI: 10.3389/fonc.2024.1385425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Accepted: 05/13/2024] [Indexed: 06/18/2024] Open
Abstract
Background The association between objective imaging response and first line immune checkpoint inhibitor (ICI) therapy regimes in advanced melanoma remains uncharacterized in routine practice. Methods We conducted a multi-center retrospective cohort analysis of advanced melanoma patients receiving first line ICI therapy from August 2013-May 2020 in Alberta, Canada. The primary outcome was likelihood of RECIST v1.1 assessed objective imaging response between patients receiving anti-programmed cell death protein 1 (anti-PD1) monotherapy and those receiving combination ipilimumab-nivolumab. Secondary outcomes were identification of baseline characteristics associated with non-response and the association of imaging response with overall survival (OS) and time to next treatment (TTNT). Results 198 patients were included, 41/198 (20.7%) had complete response, 86/198 (43.4%) had partial response, 23/198 (11.6%) had stable disease, and 48/198 (24.2%) had progressive disease. Median OS was not reached (NR) (95% CI 49.0-NR) months for complete responders, NR (95%CI 52.9-NR) months for partial responders, 33.7 (95%CI 15.8-NR) months for stable disease, and 6.4 (95%CI 5.2-10.1) months for progressive disease (log-rank p<0.001). Likelihood of objective imaging response remained similar between anti-PD1 monotherapy and ipilimumab-nivolumab groups (OR 1.95 95%CI 0.85-4.63, p=0.121). Elevated LDH level (OR 0.46; 95%CI 0.21-0.98, p=0.043), mucosal primary site (OR 0.14; 95%CI 0.03-0.48, p=0.003), and BRAF V600E mutation status (OR 0.31; 95%CI 0.13-0.72, p=0.007) were associated with decreased likelihood of response. Conclusion No significant difference in likelihood of imaging response between anti-PD1 monotherapy and combination ipilimumab-nivolumab was observed. Elevated LDH level, mucosal primary site, and BRAF V600E mutation status were associated with decreased likelihood of response. Given that pivotal clinical trials of ipilimumab-nivolumab did not formally compare ipilimumab-nivolumab with nivolumab monotherapy, this work adds context to differences in outcomes when these agents are used. These results may inform treatment selection, and aid in counseling of patients treated with first-line ICI therapy in routine clinical practice settings.
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Affiliation(s)
- Mehul Gupta
- Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Tom Baker Cancer Centre, Calgary, AB, Canada
| | - Igor Stukalin
- Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Tom Baker Cancer Centre, Calgary, AB, Canada
| | - Daniel E Meyers
- Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Tom Baker Cancer Centre, Calgary, AB, Canada
| | - Daniel Y C Heng
- Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Tom Baker Cancer Centre, Calgary, AB, Canada
| | - Jose Monzon
- Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Tom Baker Cancer Centre, Calgary, AB, Canada
| | - Tina Cheng
- Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Tom Baker Cancer Centre, Calgary, AB, Canada
| | - Vishal Navani
- Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Tom Baker Cancer Centre, Calgary, AB, Canada
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Sabaghian A, Shamsabadi S, Momeni S, Mohammadikia M, Mohebbipour K, Sanami S, Ahmad S, Akhtar N, Sharma NR, Kushwah RBS, Gupta Y, Prakash A, Pazoki-Toroudi H. The role of PD-1/PD-L1 signaling pathway in cancer pathogenesis and treatment: a systematic review. JOURNAL OF CANCER METASTASIS AND TREATMENT 2024. [DOI: 10.20517/2394-4722.2024.15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/12/2025]
Abstract
Aim: Cancer as a complex disease poses significant challenges for both diagnosis and treatment. Researchers have been exploring various avenues to find effective therapeutic strategies, with a particular emphasis on cellular signaling pathways and immunotherapy. One such pathway that has recently been suggested is the PD-1/PD-L1 pathway, which is an immune checkpoint signaling system that plays an important role in regulating the immune system and maintaining tissue homeostasis. Cancer cells exploit this pathway by producing PD-L1, which attaches to PD-1 on T cells, thus inhibiting immune responses and enabling the cancer cells to escape detection by the immune system. This study aimed to evaluate the role of the PD-1/PD-L1 pathway in cancer pathogenesis and treatment. Method: This study was performed based on the principles of Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). All in vitro , in vivo , and clinical studies that were published in English have been considered during a thorough search of the Scopus, Web of Science, and PubMed databases without date restriction until March 2024. Results: According to the studies reviewed, the PD-1/PD-L1 signaling axis suggests promising therapeutic effects on various types of cancers such as non-small cell lung cancer, melanoma, breast cancer, hepatocellular carcinoma, squamous cell carcinoma, and colorectal cancer, among others. Additionally, research suggests that immune checkpoint inhibitors that block PD1/PD-L1, such as pembrolizumab, atezolizumab, nivolumab, durvalumab, cemiplimab, avelumab, etc. , can effectively prevent tumor cells from escaping the immune system. Moreover, there might be a possible interaction between microbiome, obesity, etc. on immune mechanisms and on the immune checkpoint inhibitors (ICIs). Conclusion: Although we have gained considerable knowledge about ICIs, we are still facing challenges in effectively prescribing the appropriate ICIs for individual patients. This is largely due to the complex interactions between different intracellular pathways, which need to be thoroughly studied. To resolve this issue, it is necessary to conduct more reliable clinical trials that can produce a scientific consensus.
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Choi SH, Mani M, Kim J, Cho WJ, Martin TFJ, Kim JH, Chu HS, Jeong WJ, Won YW, Lee BJ, Ahn B, Kim J, Jeon DY, Park JW. DRG2 is required for surface localization of PD-L1 and the efficacy of anti-PD-1 therapy. Cell Death Discov 2024; 10:260. [PMID: 38802348 PMCID: PMC11130180 DOI: 10.1038/s41420-024-02027-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 04/10/2024] [Accepted: 05/14/2024] [Indexed: 05/29/2024] Open
Abstract
More than half of tumor patients with high PD-L1 expression do not respond to anti-PD-1/PD-L1 therapy, and the underlying mechanisms are yet to be clarified. Here we show that developmentally regulated GTP-binding protein 2 (DRG2) is required for response of PD-L1-expressing tumors to anti-PD-1 therapy. DRG2 depletion enhanced IFN-γ signaling and increased the PD-L1 level in melanoma cells. However, it inhibited recycling of endosomal PD-L1 and reduced surface PD-L1 levels, which led to defects in interaction with PD-1. Anti-PD-1 did not expand effector-like T cells within DRG2-depleted tumors and failed to improve the survival of DRG2-depleted tumor-bearing mice. Cohort analysis revealed that patients bearing melanoma with low DRG2 protein levels were resistant to anti-PD-1 therapy. These findings identify DRG2 as a key regulator of recycling of endosomal PD-L1 and response to anti-PD-1 therapy and provide insights into how to increase the correlation between PD-L1 expression and response to anti-PD-1 therapy.
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Affiliation(s)
- Seong Hee Choi
- Department of Biological Sciences, University of Ulsan, Ulsan, Korea
- RopheLBio, B102, Seoul Forest M Tower, Seoul, Korea
| | - Muralidharan Mani
- Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA
| | - Jeonghwan Kim
- School of System Biomedical Science, Soongsil University, Seoul, Korea
| | - Wha Ja Cho
- Department of Biological Sciences, University of Ulsan, Ulsan, Korea
| | - Thomas F J Martin
- Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA
| | - Jee Hyun Kim
- RopheLBio, B102, Seoul Forest M Tower, Seoul, Korea
| | - Hun Su Chu
- RopheLBio, B102, Seoul Forest M Tower, Seoul, Korea
| | | | - Young-Wook Won
- RopheLBio, B102, Seoul Forest M Tower, Seoul, Korea
- Department of Biomedical Engineering, University of North Texas, Denton, TX, USA
| | - Byung Ju Lee
- Department of Biological Sciences, University of Ulsan, Ulsan, Korea
- Basic-Clinic Convergence Research Institute, University of Ulsan, Ulsan, Korea
| | - Byungyong Ahn
- Basic-Clinic Convergence Research Institute, University of Ulsan, Ulsan, Korea
- Department of Food Science and Nutrition, University of Ulsan, Ulsan, Korea
| | - Junil Kim
- School of System Biomedical Science, Soongsil University, Seoul, Korea.
| | - Do Yong Jeon
- Department of Biological Sciences, University of Ulsan, Ulsan, Korea.
| | - Jeong Woo Park
- Department of Biological Sciences, University of Ulsan, Ulsan, Korea.
- Basic-Clinic Convergence Research Institute, University of Ulsan, Ulsan, Korea.
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48
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Hinton AO, N'jai AU, Vue Z, Wanjalla C. Connection Between HIV and Mitochondria in Cardiovascular Disease and Implications for Treatments. Circ Res 2024; 134:1581-1606. [PMID: 38781302 PMCID: PMC11122810 DOI: 10.1161/circresaha.124.324296] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/25/2024]
Abstract
HIV infection and antiretroviral therapy alter mitochondrial function, which can progressively lead to mitochondrial damage and accelerated aging. The interaction between persistent HIV reservoirs and mitochondria may provide insight into the relatively high rates of cardiovascular disease and mortality in persons living with HIV. In this review, we explore the intricate relationship between HIV and mitochondrial function, highlighting the potential for novel therapeutic strategies in the context of cardiovascular diseases. We reflect on mitochondrial dynamics, mitochondrial DNA, and mitochondrial antiviral signaling protein in the context of HIV. Furthermore, we summarize how toxicities related to early antiretroviral therapy and current highly active antiretroviral therapy can contribute to mitochondrial dysregulation, chronic inflammation, and poor clinical outcomes. There is a need to understand the mechanisms and develop new targeted therapies. We further consider current and potential future therapies for HIV and their interplay with mitochondria. We reflect on the next-generation antiretroviral therapies and HIV cure due to the direct and indirect effects of HIV persistence, associated comorbidities, coinfections, and the advancement of interdisciplinary research fields. This includes exploring novel and creative approaches to target mitochondria for therapeutic intervention.
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Affiliation(s)
- Antentor O Hinton
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN (A.O.H., Z.V.)
| | - Alhaji U N'jai
- Biological Sciences, Fourah Bay College and College of Medicine and Allied Health Sciences (COMAHS), University of Sierra Leone, Freetown, Sierra Leone and Koinadugu College, Kabala (A.U.N.)
| | - Zer Vue
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN (A.O.H., Z.V.)
| | - Celestine Wanjalla
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (C.W.)
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Yokota K, Takenouchi T, Fujisawa Y, Fukushima S, Uchi H, Inozume T, Kiyohara Y, Uhara H, Nakagawa K, Furukawa H, Han S, Watanabe M, Noguchi K, Yamazaki N. Long-term follow-up results from KEYNOTE-041: Phase 1b study of pembrolizumab in Japanese patients with advanced melanoma. J Dermatol 2024; 51:632-642. [PMID: 38529706 PMCID: PMC11483956 DOI: 10.1111/1346-8138.17002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 09/27/2023] [Accepted: 09/28/2023] [Indexed: 03/27/2024]
Abstract
Pembrolizumab demonstrated an acceptable safety profile and promising antitumor activity in Japanese patients with advanced melanoma in the phase 1b KEYNOTE-041 (Study of Pembrolizumab [MK-3475] in Participants With Advanced Melanoma) trial. To evaluate the long-term efficacy and safety of pembrolizumab in Japanese patients with advanced melanoma in KEYNOTE-041. The current analysis reports results of additional follow-up of approximately 12 months since the initial analysis. Eligible patients had locally advanced (unresectable stage III) or metastatic (stage IV) melanoma not amenable to local therapy and had received two or fewer prior systemic therapies. Pembrolizumab 2 mg/kg was given every 3 weeks for up to 2 years or until confirmed progression or unacceptable toxicity. Primary end points included safety, tolerability, and overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 by independent central review. The data cutoff for this analysis was August 30, 2017. Forty-two patients were followed up for a median of 22.3 months (range, 2.63-30.82 months). The ORR was 24.3% (nine of 37 evaluable patients [95% confidence interval (CI), 11.8%-41.2%]). Two patients with partial response at the time of the initial analysis achieved complete response. The median overall survival (OS) was 25.1 months (95% CI, 13.1-not reached] and the 30-month OS rate was 46.3% (95% CI, 29.8%-61.3%). The median duration of response was not reached. Treatment-related adverse events (TRAEs) were reported in 78.6% of patients; the incidence of grade 3 to 5 TRAEs was 23.8%. No additional treatment-related deaths occurred since the initial analysis. Pembrolizumab provided durable antitumor activity and an acceptable safety profile in Japanese patients with advanced melanoma.
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MESH Headings
- Humans
- Melanoma/drug therapy
- Melanoma/mortality
- Melanoma/pathology
- Antibodies, Monoclonal, Humanized/adverse effects
- Antibodies, Monoclonal, Humanized/administration & dosage
- Antibodies, Monoclonal, Humanized/therapeutic use
- Male
- Female
- Middle Aged
- Aged
- Skin Neoplasms/drug therapy
- Skin Neoplasms/pathology
- Skin Neoplasms/mortality
- Follow-Up Studies
- Adult
- Japan
- Antineoplastic Agents, Immunological/therapeutic use
- Antineoplastic Agents, Immunological/adverse effects
- Antineoplastic Agents, Immunological/administration & dosage
- Neoplasm Staging
- Aged, 80 and over
- Treatment Outcome
- East Asian People
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Affiliation(s)
- Kenji Yokota
- Department of DermatologyNagoya University Graduate School of MedicineNagoyaJapan
| | | | - Yasuhiro Fujisawa
- Department of Dermatology, Faculty of MedicineEhime UniversityEhimeJapan
| | - Satoshi Fukushima
- Department of Dermatology and Plastic Surgery, Faculty of Life SciencesKumamoto UniversityKumamotoJapan
| | - Hiroshi Uchi
- Department of Dermatologic Oncology, National Hospital Organization Kyusyu Cancer CenterFukuokaJapan
| | | | - Yoshio Kiyohara
- Division of DermatologyShizuoka Cancer Center HospitalShizuokaJapan
| | - Hisashi Uhara
- Department of DermatologySapporo Medical University, School of MedicineSapporoHokkaidoJapan
| | - Kazuhiko Nakagawa
- Department of Medical Oncology, Faculty of MedicineKindai UniversityOsakaJapan
| | - Hiroshi Furukawa
- Department of Plastic and Reconstructive SurgeryAichi Medical University HospitalNagakuteAichiJapan
| | | | | | | | - Naoya Yamazaki
- Department of Dermatologic OncologyNational Cancer Center HospitalTokyoJapan
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50
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Wang Y, Pattarayan D, Huang H, Zhao Y, Li S, Wang Y, Zhang M, Li S, Yang D. Systematic investigation of chemo-immunotherapy synergism to shift anti-PD-1 resistance in cancer. Nat Commun 2024; 15:3178. [PMID: 38609378 PMCID: PMC11015024 DOI: 10.1038/s41467-024-47433-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 04/02/2024] [Indexed: 04/14/2024] Open
Abstract
Chemo-immunotherapy combinations have been regarded as one of the most practical ways to improve immunotherapy response in cancer patients. In this study, we integrate the transcriptomics data from anti-PD-1-treated tumors and compound-treated cancer cell lines to systematically screen for chemo-immunotherapy synergisms in silico. Through analyzing anti-PD-1 induced expression changes in patient tumors, we develop a shift ability score to measure if a chemotherapy or a small molecule inhibitor treatment can shift anti-PD-1 resistance in tumor cells. By applying shift ability analysis to 41,321 compounds and 16,853 shRNA treated cancer cell lines transcriptomic data, we characterize the landscape of chemo-immunotherapy synergism and experimentally validated a mitochondrial RNA-dependent mechanism for drug-induced immune activation in tumor. Our study represents an effort to mechanistically characterize chemo-immunotherapy synergism and will facilitate future pre-clinical and clinical studies.
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Affiliation(s)
- Yue Wang
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Dhamotharan Pattarayan
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Haozhe Huang
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Yueshan Zhao
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Sihan Li
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Yifei Wang
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Min Zhang
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Song Li
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Da Yang
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
- UPMC Hillman Cancer Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
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