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Abdul-Razek N, Khalil RG, Abdel-Latif M, Kamel MM, Alhazza IM, Awad EM, Ebaid H, Abuelsaad ASA. Investigating the Tumor-Suppressive, Antioxidant Effects and Molecular Binding Affinity of Quercetin-Loaded Selenium Nanoparticles in Breast Cancer Cells. BIONANOSCIENCE 2025; 15:135. [DOI: 10.1007/s12668-024-01767-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/09/2024] [Indexed: 01/03/2025]
Abstract
AbstractIn 2023, breast cancer is expected to have nearly 2 million new cases, making it the second most common cancer overall and the most prevalent among women. Multidrug resistance limits the effectiveness of chemotherapy; however, quercetin, a natural flavonoid, helps combat this issue. The goal of the current investigation is to determine the impact of a novel composite of quercetin and selenium nanoparticles (SeNPs) on the breast cancer cell lines MDA-MB-231 and MCF-7 in order to enhance quercetin’s tumor-suppressive action and decrease selenium (Se) toxicity. Particle size, zeta potential, FTIR, SEM, UV–VIS spectroscopy, and EDX were used to characterize quercetin-selenium nanoparticles (Que-SeNPs), in addition to evaluation of the antioxidant, apoptotic, and anticancer properties. Moreover, autophagy (Atg-13) protein receptors and PD-1/PD-L1 checkpoint were targeted using molecular docking modeling and molecular dynamics (MD) simulations to assess the interaction stability between Que-SeNPs and three targets: PDL-1, PD-1, and Atg-13HORMA domain. Que-SeNPs, synthesized with quercetin, were stable, semi-spherical (80–117 nm), and had a zeta potential of − 37.8 mV. They enhanced cytotoxicity, antioxidant activity, and apoptosis compared to quercetin alone in MCF-7 and MDA-MB-231 cells. Docking simulations showed strong binding to the PD-1/PD-L1 checkpoint and Atg-13HORMA protein receptors. Moreover, the molecular dynamics simulation revealed that the behavior of the PD-L1 intriguing insights into its structural dynamics, therefore, suggesting a stable phase where the complex is adjusting to the simulation environment. The present data confirmed that the stable formula of Que-SeNPs is cytotoxic, antioxidant, and has a potential activity to increase apoptosis in breast cancer cells, with the potential to inhibit PD-1/PD-L1 and Atg-13 proteins.
Graphical Abstract
Role of Que-SeNPs on breast cancer cells in vitro against two breast cancer cell lines MDA-MB-231 and MCF-7.
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Naei VY, Tubelleza R, Monkman J, Sadeghirad H, Donovan ML, Blick T, Wicher A, Bodbin S, Viratham A, Stad R, Basu S, Cooper C, Barnett C, O'Byrne K, Ladwa R, Warkiani ME, Hughes BGM, Kulasinghe A. Spatial interaction mapping of PD-1/PD-L1 in head and neck cancer reveals the role of macrophage-tumour barriers associated with immunotherapy response. J Transl Med 2025; 23:177. [PMID: 39939997 PMCID: PMC11818323 DOI: 10.1186/s12967-025-06186-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: 10/22/2024] [Accepted: 01/29/2025] [Indexed: 02/14/2025] Open
Abstract
BACKGROUND Mucosal head and neck squamous cell carcinoma (HNSCC) is often diagnosed at an advanced stage, where the prognosis is poor due to the high rates of recurrence and metastasis. With approximately one million new cases projected in 2024, worldwide mortality of HNSCC is estimated to reach 50% of detected cases the same year. Patients with early-stage tumours showed a 50-60% five-year survival rate in the US. Immune checkpoint inhibitors (ICIs) have shown promising results in prolonging survival in a subset of patients with recurrent or metastatic disease. However, challenges remain, particularly the limited efficacy of PD-1/PD-L1 blockade therapies. PD-L1 protein expression has been shown to be limited in its predictive power for ICI therapies. Emerging evidence shows that intricate characterisation of the tumour microenvironment (TME) is fundamental to understand interacting cells. This study aims to bridge the gap in understanding the tumor microenvironment by identifying distinct spatial patterns of PD-1/PD-L1 interactions and their association with immunotherapy responses in head and neck squamous cell carcinoma (HNSCC). METHODS In this study, we sought to apply a more nuanced approach to understanding cellular interactions by mapping PD-1/PD-L1 interactions across whole-slide HNSCC tissue samples collected prior to ICI therapy. We used a combination of spatial proteomics (Akoya Biosciences) and an in situ proximity ligation assay (isPLA, Navinci Diagnostics) to visualise PD-1/PD-L1 interactions across cell types and cellular neighbourhoods within the tumour TME. RESULTS Our findings indicate the existence of isPLA+ PD-1/PD-L1 interactions between macrophages/CD3 T cell-enriched neighbourhoods and tumour cells at the tumour-stroma boundaries in ICI-resistant tumours. The presence of these dense macrophage-tumour layers, which are either absent or dispersed in responders, indicates a barrier that may restrict immune cell infiltration and promote immune escape mechanisms. In contrast, responders had abundant B and T cell aggregates, predominantly around the tumour edges linked to enhanced immune responses to ICI therapy and better clinical outcomes. CONCLUSION This study highlights the utility of isPLA in detecting distinct tumour-immune interactions within the TME, offering new cellular interaction metrics for stratifying and optimising immunotherapy strategies.
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Affiliation(s)
- Vahid Yaghoubi Naei
- School of Biomedical Engineering, University of Technology Sydney, Sydney, NSW, Australia
- Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
| | - Rafael Tubelleza
- Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
- Queensland Spatial Biology Centre, Wesley Research Institute, The Wesley Hospital, Brisbane, Australia
| | - James Monkman
- Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
- Queensland Spatial Biology Centre, Wesley Research Institute, The Wesley Hospital, Brisbane, Australia
| | - Habib Sadeghirad
- Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
| | - Meg L Donovan
- Queensland Spatial Biology Centre, Wesley Research Institute, The Wesley Hospital, Brisbane, Australia
| | - Tony Blick
- Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
| | | | | | | | | | | | | | | | - Ken O'Byrne
- The Princess Alexandra Hospital, Brisbane, Australia
| | - Rahul Ladwa
- The Princess Alexandra Hospital, Brisbane, Australia
| | | | - Brett G M Hughes
- The Royal Brisbane and Women's Hospital, Brisbane, Australia
- School of Medicine, University of Queensland, Brisbane, Australia
| | - Arutha Kulasinghe
- Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia.
- Queensland Spatial Biology Centre, Wesley Research Institute, The Wesley Hospital, Brisbane, Australia.
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Liang A, Wu Z, Zhuo T, Zhu Y, Li Z, Chen S, Dai L, Wang Y, Tan X, Chen M. TONSL promotes lung adenocarcinoma progression, immune escape and drug sensitivity. Clin Transl Oncol 2025; 27:518-533. [PMID: 39097545 DOI: 10.1007/s12094-024-03627-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: 05/03/2024] [Accepted: 07/19/2024] [Indexed: 08/05/2024]
Abstract
PURPOSE The tonsoku-like DNA repair protein (TONSL) encoded by the TONSL gene, located on chromosome 8q24.3, is crucial for repairing DNA double-strand breaks through homologous recombination. However, TONSL overexpression in lung adenocarcinoma (LUAD) promotes tumor development, leading to a poor prognosis. METHODS TONSL was verified as a reliable prognostic marker for LUAD using bioinformatics, and clinical features related to LUAD prognosis were screened from the TCGA database to establish the relationship between risk factors and TONSL expression. In addition, TONSL expression in normal and LUAD tissues was verified using real-time quantitative polymerase chain reaction and immunohistochemistry. To elucidate the possible functions of TONSL, TONSL-related differentially expressed genes were screened, and functional enrichment analysis was performed. Subsequently, siRNA was used to knock down TONSL expression in lung cancer cells for cytobehavioral experiments. The effects of TONSL expression on tumor immune escape were analyzed using the ESTIMATE algorithm and tumor immune-infiltration analysis. In addition, the half-maximal inhibitory concentration of LUAD with varying TONSL expression levels in response to first-line chemotherapeutic drugs and epidermal growth factor receptor-tyrosine kinase inhibitors was analyzed for drug sensitivity. RESULTS Up-regulation of TONSL in LUAD promotes the proliferation, migration, and invasion of lung cancer cells, thereby contributing to a poor prognosis. Furthermore, TONSL overexpression promotes immune escape and drug sensitivity in LUAD. CONCLUSION TONSL serves as a reliable prognostic marker for LUAD, and its up-regulation is associated with increased immune escape and drug sensitivity. These findings suggest that TONSL holds potential as a novel therapeutic target for LUAD.
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Affiliation(s)
- Anru Liang
- Department of Cardio-Thoracic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Zuotao Wu
- Department of Cardio-Thoracic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Ting Zhuo
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Yongjie Zhu
- Department of Cardio-Thoracic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Zihao Li
- Department of Cardio-Thoracic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Sirong Chen
- Department of Radiotherapy, Guangxi Medical University Cancer Hospital, No. 71 Hedi Rd, Nanning, 530021, Guangxi Zhuang Autonomous Region, China
| | - Lei Dai
- Department of Cardio-Thoracic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Yongyong Wang
- Department of Cardio-Thoracic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Xiang Tan
- Department of Cardio-Thoracic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China.
| | - Mingwu Chen
- Department of Cardio-Thoracic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China.
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Abdelazeem KNM, Nguyen D, Corbo S, Darragh LB, Matsumoto MW, Van Court B, Neupert B, Yu J, Olimpo NA, Osborne DG, Gadwa J, Ross RB, Nguyen A, Bhatia S, Kapoor M, Friedman RS, Jacobelli J, Saviola AJ, Knitz MW, Pasquale EB, Karam SD. Manipulating the EphB4-ephrinB2 axis to reduce metastasis in HNSCC. Oncogene 2025; 44:130-146. [PMID: 39489818 PMCID: PMC11725500 DOI: 10.1038/s41388-024-03208-9] [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: 07/06/2024] [Revised: 10/19/2024] [Accepted: 10/23/2024] [Indexed: 11/05/2024]
Abstract
The EphB4-ephrinB2 signaling axis has been heavily implicated in metastasis across numerous cancer types. Our emerging understanding of the dichotomous roles that EphB4 and ephrinB2 play in head and neck squamous cell carcinoma (HNSCC) poses a significant challenge to rational drug design. We find that EphB4 knockdown in cancer cells enhances metastasis in preclinical HNSCC models by augmenting immunosuppressive cells like T regulatory cells (Tregs) within the tumor microenvironment. EphB4 inhibition in cancer cells also amplifies their ability to metastasize through increased expression of genes associated with hallmark pathways of metastasis along with classical and non-classical epithelial-mesenchymal transition. In contrast, vascular ephrinB2 knockout coupled with radiation therapy (RT) enhances anti-tumor immunity, reduces Treg accumulation into the tumor, and decreases metastasis. Notably, targeting the EphB4-ephrinB2 signaling axis with the engineered ligands ephrinB2-Fc-His and Fc-TNYL-RAW-GS reduces local tumor growth and distant metastasis in a preclinical model of HNSCC. Our data suggests that targeted inhibition of vascular ephrinB2 while avoiding inhibition of EphB4 in cancer cells could be a promising strategy to mitigate HNSCC metastasis.
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Affiliation(s)
- Khalid N M Abdelazeem
- Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
- Radiation Biology Research Department, National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority, Cairo, Egypt
| | - Diemmy Nguyen
- Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - Sophia Corbo
- Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - Laurel B Darragh
- Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
- Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Mike W Matsumoto
- Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Benjamin Van Court
- Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - Brooke Neupert
- Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - Justin Yu
- Department of Otolaryngology - Head and Neck Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Nicholas A Olimpo
- Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - Douglas Grant Osborne
- Department of Dermatology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Jacob Gadwa
- Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
- Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Richard B Ross
- Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - Alexander Nguyen
- Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - Shilpa Bhatia
- Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - Mohit Kapoor
- Krembil Research Institute, University Health Network, and University of Toronto, Toronto, ON, Canada
| | - Rachel S Friedman
- Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Barbara Davis Research Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Jordan Jacobelli
- Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Barbara Davis Research Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Anthony J Saviola
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Center, Aurora, CO, USA
| | - Michael W Knitz
- Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - Elena B Pasquale
- Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Sana D Karam
- Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.
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Cao X, Wan S, Wu B, Liu Z, Xu L, Ding Y, Huang H. Antitumor Research Based on Drug Delivery Carriers: Reversing the Polarization of Tumor-Associated Macrophages. Mol Pharm 2025. [PMID: 39868820 DOI: 10.1021/acs.molpharmaceut.4c01277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2025]
Abstract
The development of malignant tumors is a complex process that involves the tumor microenvironment (TME). An immunosuppressive TME presents significant challenges to current cancer therapies, serving as a key mechanism through which tumor cells evade immune detection and play a crucial role in tumor progression and metastasis. This impedes the optimal effectiveness of immunotherapeutic approaches, including cytokines, immune checkpoint inhibitors, and cancer vaccines. Tumor-associated macrophages (TAMs), a major component of tumor-infiltrating immune cells, exhibit dual functionalities: M1-like TAMs suppress tumorigenesis, while M2-like TAMs promote tumor growth and metastasis. Consequently, the development of various nanocarriers aimed at polarizing M2-like TAMs to M1-like phenotypes through distinct mechanisms has emerged as a promising therapeutic strategy to inhibit tumor immune escape and enhance antitumor responses. This Review covers the origin and types of TAMs, common pathways regulating macrophage polarization, the role of TAMs in tumor progression, and therapeutic strategies targeting TAMs, aiming to provide a comprehensive understanding and guidance for future research and clinical applications.
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Affiliation(s)
- Xinyu Cao
- Department of Pharmaceutics, School of Pharmacy, Nantong University, Nantong 226001, China
| | - Shen Wan
- Department of Pharmaceutics, School of Pharmacy, Nantong University, Nantong 226001, China
| | - Bingyu Wu
- Department of Pharmaceutics, School of Pharmacy, Nantong University, Nantong 226001, China
| | - Zhikuan Liu
- Department of Pharmaceutics, School of Pharmacy, Nantong University, Nantong 226001, China
| | - Lixing Xu
- Department of Pharmaceutics, School of Pharmacy, Nantong University, Nantong 226001, China
| | - Yu Ding
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, School of Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Haiqin Huang
- Department of Pharmaceutics, School of Pharmacy, Nantong University, Nantong 226001, China
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Yang F, Dan M, Shi J, Fan L, Zhang H, Jian T, Lei K, Wang Y, Xin J, Yu Z, Chen W. Efficacy and safety of PD-1 inhibitors as second-line treatment for advanced squamous esophageal cancer: a systematic review and network meta-analysis with a focus on PD-L1 expression levels. Front Immunol 2025; 15:1510145. [PMID: 39916953 PMCID: PMC11798917 DOI: 10.3389/fimmu.2024.1510145] [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: 10/12/2024] [Accepted: 12/27/2024] [Indexed: 02/09/2025] Open
Abstract
Background PD-1 inhibitors have shown promising efficacy in enhancing OS and AEs as second-line therapies for patients with advanced esophageal squamous cell carcinoma (ESCC). However, there remains no clear consensus on which PD-1 inhibitor provides the best balance between efficacy and safety. To address this key issue in the second-line treatment of ESCC, we conducted a network meta-analysis (NMA) with a focus on OS benefits, particularly in patients with different levels of PD-L1 expression. Methods A systematic search of relevant literature was conducted in Web of Science, Embase, PubMed, and Cochrane Library, covering publications from the inception of these database to June 2024. The evaluated endpoints included OS, progression-free survival (PFS), objective response rate (ORR), AEs, and Grade ≥ 3 adverse events (Grade ≥ 3 AEs). A systematic review and Bayesian network meta-analysis were performed to assess the efficacy and safety of various immunotherapy regimens in patients with advanced ESCC. To ensure transparency, novelty, and reliability, this study was prospectively registered in the systematic review registry (CRD42024540581). Results Five randomized controlled trials (RCTs), encompassing 2,078 patients and six treatment regimens, were included in this study. Among advanced ESCC patients not selected based on PD-L1 expression, Sintilimab demonstrated the greatest OS benefit (HR = 0.70, 95% CI: 0.50-0.98). Camrelizumab showed the most favorable improvement in PFS compared to chemotherapy (HR = 0.64, 95% CI: 0.47-0.87) and also achieved the best ORR benefit (OR = 3.72, 95% CI: 1.98-6.99). In terms of safety, Nivolumab (OR = 0.10, 95% CI: 0.05-0.19) and Tislelizumab (OR = 0.18, 95% CI: 0.10-0.33) exhibited significant safety advantages over chemotherapy concerning AEs. Moreover, Nivolumab (OR = 0.13, 95% CI: 0.08-0.20) was associated with a markedly lower risk of Grade ≥ 3 AEs compared to chemotherapy. Subgroup analysis based on PD-L1 expression revealed that Tislelizumab (HR = 0.53, 95% CI: 0.37-0.76) offered the greatest OS benefit for patients with PD-L1 ≥ 10%, while Camrelizumab (HR = 0.71, 95% CI: 0.57-0.89) was the most likely regimen to provide an OS advantage for patients with PD-L1 < 10%. Conclusion Compared to chemotherapy, PD-1 inhibitors may provide improved survival outcomes for patients with advanced ESCC. Among patients not selected based on PD-L1 expression, Sintilimab is most likely to deliver the best survival benefit. For patients with PD-L1 expression ≥ 10%, Tislelizumab is expected to offer the greatest efficacy, while Camrelizumab appears to be the most effective for those with PD-L1 < 10%. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024540581.
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Affiliation(s)
- Fei Yang
- Department of Pharmacy, Ya ‘an People’s Hospital, Ya ‘an, China
| | - Min Dan
- Department of Pharmacy, Ya ‘an People’s Hospital, Ya ‘an, China
| | - Jindan Shi
- Department of Pharmacy, Ya ‘an People’s Hospital, Ya ‘an, China
| | - Ling Fan
- Department of Pharmacy, Ya ‘an People’s Hospital, Ya ‘an, China
| | - Haoluo Zhang
- Department of Pharmacy, Ya ‘an People’s Hospital, Ya ‘an, China
| | - Tiantian Jian
- Department of Pharmacy, Ya ‘an People’s Hospital, Ya ‘an, China
| | - Kelu Lei
- Department of Pharmacy, Ya ‘an People’s Hospital, Ya ‘an, China
| | - Yue Wang
- Department of Pharmacy, Ya ‘an People’s Hospital, Ya ‘an, China
| | - Juan Xin
- Department of Pharmacy, Ya ‘an People’s Hospital, Ya ‘an, China
| | - Zhigang Yu
- Department of Pharmacy, Ya ‘an People’s Hospital, Ya ‘an, China
| | - Wei Chen
- Department of Pharmacy, Emergency General Hospital, Beijing, China
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Devasani JR, Guntuku G, Panatula N, Muthyala MKK, Palla MS, Siahaan TJ. Innovative CDR grafting and computational methods for PD-1 specific nanobody design. FRONTIERS IN BIOINFORMATICS 2025; 4:1488331. [PMID: 39897125 PMCID: PMC11782559 DOI: 10.3389/fbinf.2024.1488331] [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: 08/29/2024] [Accepted: 12/30/2024] [Indexed: 02/04/2025] Open
Abstract
Introduction The development of nanobodies targeting Programmed Cell Death Protein-1 (PD-1) offers a promising approach in cancer immunotherapy. This study aims to design and characterize a PD-1-specific nanobody using an integrated computational and experimental approach. Methods An in silico design strategy was employed, involving Complementarity-Determining Region (CDR) grafting to construct the nanobody sequence. The three-dimensional structure of the nanobody was predicted using AlphaFold2, and molecular docking simulations via ClusPro were conducted to evaluate binding interactions with PD-1. Physicochemical properties, including stability and solubility, were analyzed using web-based tools, while molecular dynamics (MD) simulations assessed stability under physiological conditions. The nanobody was produced and purified using Ni-NTA chromatography, and experimental validation was performed through Western blotting, ELISA, and dot blot analysis. Results Computational findings demonstrated favorable binding interactions, stability, and physicochemical properties of the nanobody. Experimental results confirmed the nanobody's specific binding affinity to PD-1, with ELISA and dot blot analyses providing evidence of robust interaction. Discussion This study highlights the potential of combining computational and experimental approaches for engineering nanobodies. The engineered PD-1 nanobody exhibits promising characteristics, making it a strong candidate for further testing in cancer immunotherapy applications.
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Affiliation(s)
- Jagadeeswara Reddy Devasani
- Pharmaceutical Biotechnology Division, A.U. College of Pharmaceutical Sciences, Andhra University, Visakhapatnam, Andhra Pradesh, India
| | - Girijasankar Guntuku
- Pharmaceutical Biotechnology Division, A.U. College of Pharmaceutical Sciences, Andhra University, Visakhapatnam, Andhra Pradesh, India
| | - Nalini Panatula
- Pharmaceutical Biotechnology Division, A.U. College of Pharmaceutical Sciences, Andhra University, Visakhapatnam, Andhra Pradesh, India
| | - Murali Krishna Kumar Muthyala
- Pharmaceutical Chemistry Division, A.U. College of Pharmaceutical Sciences, Andhra University, Visakhapatnam, Andhra Pradesh, India
| | - Mary Sulakshana Palla
- GITAM School of Pharmacy, GITAM Deemed to be University, Visakhapatnam, Andhra Pradesh, India
| | - Teruna J. Siahaan
- Department of Pharmaceutical Chemistry, School of Pharmacy, The University of Kansas, Lawrence, KS, United States
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Liu S, Zhang N, Ji X, Yang S, Zhao Z, Li P. Helicobacter pylori CagA promotes gastric cancer immune escape by upregulating SQLE. Cell Death Dis 2025; 16:17. [PMID: 39809787 PMCID: PMC11733131 DOI: 10.1038/s41419-024-07318-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: 07/01/2024] [Revised: 11/27/2024] [Accepted: 12/17/2024] [Indexed: 01/16/2025]
Abstract
Helicobacter pylori (H. pylori) infection is a well-established risk factor for gastric cancer, primarily due to its virulence factor, cytotoxin-associated gene A (CagA). Although PD-L1/PD-1-mediated immune evasion is critical in cancer development, the impact of CagA on PD-L1 regulation remains unclear. This study revealed that H. pylori CagA upregulated squalene epoxidase (SQLE) expression, a key enzyme in the cholesterol biosynthesis pathway. Elevated SQLE activity increased cellular palmitoyl-CoA levels, enhancing PD-L1 palmitoylation while decreasing its ubiquitination. This ultimately increases PD-L1 stability, suppressing T cell activity and facilitating immune evasion in gastric cancer. In summary, our findings highlight the crucial role of the CagA-SQLE-PD-L1 axis in gastric cancer progression, suggesting potential therapeutic strategies for targeting CagA-positive gastric cancer.
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Affiliation(s)
- Sifan Liu
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, State Key Laboratory for Digestive Health, National Clinical Research Center of Digestive Diseases, Beijing Digestive Disease Center, Beijing, 100050, China
| | - Nan Zhang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, State Key Laboratory for Digestive Health, National Clinical Research Center of Digestive Diseases, Beijing Digestive Disease Center, Beijing, 100050, China.
| | - Xu Ji
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, State Key Laboratory for Digestive Health, National Clinical Research Center of Digestive Diseases, Beijing Digestive Disease Center, Beijing, 100050, China
| | - Shuyue Yang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, State Key Laboratory for Digestive Health, National Clinical Research Center of Digestive Diseases, Beijing Digestive Disease Center, Beijing, 100050, China
| | - Zheng Zhao
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, State Key Laboratory for Digestive Health, National Clinical Research Center of Digestive Diseases, Beijing Digestive Disease Center, Beijing, 100050, China
| | - Peng Li
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, State Key Laboratory for Digestive Health, National Clinical Research Center of Digestive Diseases, Beijing Digestive Disease Center, Beijing, 100050, China.
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Wei Y, Zhou K, Wang C, Du X, Wang Z, Chen G, Zhang H, Hui X. Exosomal miR-142-3p from M1-polarized macrophages suppresses cell growth and immune escape in glioblastoma through regulating HMGB1-mediated PD-1/PD-L1 checkpoint. J Neurochem 2025; 169:e16224. [PMID: 39289038 DOI: 10.1111/jnc.16224] [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: 02/27/2023] [Revised: 08/27/2024] [Accepted: 08/28/2024] [Indexed: 09/19/2024]
Abstract
Glioblastoma (GBM) is one of the most prevalent cancerous brain tumors. Former studies have reported that exosomes derived from M1-polarized macrophages (M1 exosomes) inhibit tumor occurrence and development through delivery of tumor suppressor genes. Also, microRNA-142-3p (miR-142-3p) has been verified to function as a tumor suppressor. GBM cell proliferation was evaluated by Cell Counting Kit-8 (CCK-8), colony formation assay and 5-ethynyl-2'-deoxyuridine (EdU) assay; cell apoptosis was determined by flow cytometry analysis and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Mechanism investigations were conducted for analyzing the molecular mechanism by which miR-142-3p and M1 exosomes affect GBM progression. Upregulation of miR-142-3p expression was detected in M1-polarized macrophages and M1 exosomes. M1 exosomes inhibit GBM cell proliferation and trigger cell apoptosis. Functionally, miR-142-3p silencing promotes the proliferation and inhibits the apoptosis of GBM cells treated with M1 exosomes. As for molecular mechanism, miR-142-3p inhibits GBM cell growth via targeting high-mobility group box 1 (HMGB1). In addition, miR-142-3p/HMGB1 axis affects GBM cell immune escape through modulation of programmed death-1/programmed death ligand-1 (PD-1/PD-L1) checkpoint. Our study demonstrated that exosomal miR-142-3p from M1-polarized macrophages suppresses cell growth and immune escape in GBM through regulating HMGB1-mediated PD-1/PD-L1 checkpoint.
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Affiliation(s)
- Yigong Wei
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China
| | - Kun Zhou
- Department of Neurosurgery, Jinyang Hospital Affiliated to Guizhou Medical University (Guiyang Second People's Hospital), Guiyang, China
| | - Cheng Wang
- Department of Neurosurgery, Jinyang Hospital Affiliated to Guizhou Medical University (Guiyang Second People's Hospital), Guiyang, China
| | - Xiaolin Du
- Department of Neurosurgery, Jinyang Hospital Affiliated to Guizhou Medical University (Guiyang Second People's Hospital), Guiyang, China
| | - Zhengdi Wang
- Department of Neurosurgery, Jinyang Hospital Affiliated to Guizhou Medical University (Guiyang Second People's Hospital), Guiyang, China
| | - Guangtang Chen
- Department of Neurosurgery, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Huan Zhang
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China
| | - Xuhui Hui
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China
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10
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Ahmad I, Altameemi KKA, Hani MM, Ali AM, Shareef HK, Hassan ZF, Alubiady MHS, Al-Abdeen SHZ, Shakier HG, Redhee AH. Shifting cold to hot tumors by nanoparticle-loaded drugs and products. Clin Transl Oncol 2025; 27:42-69. [PMID: 38922537 DOI: 10.1007/s12094-024-03577-3] [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: 05/28/2024] [Accepted: 06/17/2024] [Indexed: 06/27/2024]
Abstract
Cold tumors lack antitumor immunity and are resistant to therapy, representing a major challenge in cancer medicine. Because of the immunosuppressive spirit of the tumor microenvironment (TME), this form of tumor has a low response to immunotherapy, radiotherapy, and also chemotherapy. Cold tumors have low infiltration of immune cells and a high expression of co-inhibitory molecules, such as immune checkpoints and immunosuppressive molecules. Therefore, targeting TME and remodeling immunity in cold tumors can improve the chance of tumor repression after therapy. However, tumor stroma prevents the infiltration of inflammatory cells and hinders the penetration of diverse molecules and drugs. Nanoparticles are an intriguing tool for the delivery of immune modulatory agents and shifting cold to hot tumors. In this review article, we discuss the mechanisms underlying the ability of nanoparticles loaded with different drugs and products to modulate TME and enhance immune cell infiltration. We also focus on newest progresses in the design and development of nanoparticle-based strategies for changing cold to hot tumors. These include the use of nanoparticles for targeted delivery of immunomodulatory agents, such as cytokines, small molecules, and checkpoint inhibitors, and for co-delivery of chemotherapy drugs and immunomodulatory agents. Furthermore, we discuss the potential of nanoparticles for enhancing the efficacy of cancer vaccines and cell therapy for overcoming resistance to treatment.
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Affiliation(s)
- Irfan Ahmad
- Department of Clinical Laboratory Sciences, College of Applied Medical Science, King Khalid University, Abha, Saudi Arabia.
| | | | - Mohaned Mohammed Hani
- Department of Medical Instrumentation Engineering Techniques, Imam Ja'afar Al-Sadiq University, Al Muthanna, Iraq
| | - Afaq Mahdi Ali
- Department of Pharmaceutics, Al-Turath University College, Baghdad, Iraq
| | - Hasanain Khaleel Shareef
- Department of Medical Biotechnology, College of Science, Al-Mustaqbal University, Hilla, Iraq
- Biology Department, College of Science for Women, University of Babylon, Hilla, Iraq
| | | | | | | | | | - Ahmed Huseen Redhee
- Medical Laboratory Technique College, The Islamic University, Najaf, Iraq
- Medical Laboratory Technique College, The Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- Medical Laboratory Technique College, The Islamic University of Babylon, Babylon, Iraq
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11
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Dai Y, Ruan T, Yang W, Liu S, Chen J, Fang Y, Li Q. Efficacy and Safety of Paclitaxel-Based PD-1/PD-L1 Immunotherapies for Triple-Negative Breast Cancer: A Systematic Review and Network Meta-Analysis. Clin Med Insights Oncol 2024; 18:11795549241308072. [PMID: 39734512 PMCID: PMC11672372 DOI: 10.1177/11795549241308072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Accepted: 11/27/2024] [Indexed: 12/31/2024] Open
Abstract
Background Triple negative breast cancer (TNBC) is a deadly subtype of breast cancer with limited treatment options. Currently, programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors have become the first choice for breast cancer immunotherapies. Despite paclitaxel being considered a cornerstone drug in breast cancer treatment, the effectiveness, safety, and optimal drug selection for its combination with PD-1/PD-L1 inhibitors remain uncertain. Methods We conducted a systematic review and network meta-analysis, performing a comprehensive literature search across PubMed, Embase, and the Cochrane Library from the inception of each database through May 18, 2024. Selected trials were those that assessed the efficacy and safety of paclitaxel-based PD-1/PD-L1 therapies for the treatment of TNBC. The primary endpoint assessed was overall survival (OS), while secondary outcomes included progression-free survival (PFS), adverse events (AEs), overall response rate (ORR), and Pathological complete response (pCR). This study is registered in PROSPERO under registration number CRD42023429651. Results A total of 8 RCTs meeting our eligibility criteria were included, involving 4626 patients who received either Paclitaxel (Paclitaxel-placebo/chemotherapy) or a combination of durvalumab, pembrolizumab, atezolizumab, toripalimab with paclitaxel. The pooled results demonstrated that Durvalumab combined with Paclitaxel significantly reduced the hazard ratio for OS (surface under the cumulative ranking [SUCRA]: 91.05%) and PFS compared with Paclitaxel alone (SUCRA: 83.52%). Additionally, Durvalumab plus Paclitaxel significantly improved the ORR compared with Paclitaxel (odds ratio [OR]: 2.30; 95% credible interval [CrI]: 1.10-5.20). For safety outcomes, Atezolizumab plus Paclitaxel showed a favorable profile in AEs, with no significant differences observed between groups. In the pCR study, Pembrolizumab plus Paclitaxel was the most effective treatment option (SUCRA: 81.85%). Conclusions When combined with paclitaxel, PD-1/PD-L1 inhibitors exhibit a favorable survival benefit. The combination of Durvalumab and paclitaxel represents the optimal treatment option. In the future, attention should be paid to the TNBC subtypes and drug dosage, as these factors may help to design personalized TNBC treatment programs.
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Affiliation(s)
| | - Tianyin Ruan
- Institute of Hepatology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wenhui Yang
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Shan Liu
- Center of Clinical Evaluation and Analysis, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
| | - Jiahao Chen
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yingying Fang
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Qiushuang Li
- Center of Clinical Evaluation and Analysis, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
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12
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Godiyal Y, Maheshwari D, Taniguchi H, Zinzuwadia SS, Morera-Díaz Y, Tewari D, Bishayee A. Role of PD-1/PD-L1 signaling axis in oncogenesis and its targeting by bioactive natural compounds for cancer immunotherapy. Mil Med Res 2024; 11:82. [PMID: 39690423 DOI: 10.1186/s40779-024-00586-9] [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: 07/08/2024] [Accepted: 11/29/2024] [Indexed: 12/19/2024] Open
Abstract
Cancer is a global health problem and one of the leading causes of mortality. Immune checkpoint inhibitors have revolutionized the field of oncology, emerging as a powerful treatment strategy. A key pathway that has garnered considerable attention is programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1). The interaction between PD-L1 expressed on tumor cells and PD-1 reduces the innate immune response and thus compromises the capability of the body's immune system. Furthermore, it controls the phenotype and functionality of innate and adaptive immune components. A range of monoclonal antibodies, including avelumab, atezolizumab, camrelizumab, dostarlimab, durvalumab, sinitilimab, toripalimab, and zimberelimab, have been developed for targeting the interaction between PD-1 and PD-L1. These agents can induce a broad spectrum of autoimmune-like complications that may affect any organ system. Recent studies have focused on the effect of various natural compounds that inhibit immune checkpoints. This could contribute to the existing arsenal of anticancer drugs. Several bioactive natural agents have been shown to affect the PD-1/PD-L1 signaling axis, promoting tumor cell apoptosis, influencing cell proliferation, and eventually leading to tumor cell death and inhibiting cancer progression. However, there is a substantial knowledge gap regarding the role of different natural compounds targeting PD-1 in the context of cancer. Hence, this review aims to provide a common connection between PD-1/PD-L1 blockade and the anticancer effects of distinct natural molecules. Moreover, the primary focus will be on the underlying mechanism of action as well as the clinical efficacy of bioactive molecules. Current challenges along with the scope of future research directions targeting PD-1/PD-L1 interactions through natural substances are also discussed.
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Affiliation(s)
- Yogesh Godiyal
- Department of Pharmacognosy and Phytochemistry, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, New Delhi, 110017, India
| | - Drishti Maheshwari
- Department of Pharmacognosy and Phytochemistry, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, New Delhi, 110017, India
| | - Hiroaki Taniguchi
- Department of Experimental Embryology, Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, Jastrzebiec, 05-552, Magdalenka, Poland
- African Genome Center, Mohammed VI Polytechnic University, Hay Moulay Rachid, 43150, Ben Guerir, Morocco
| | - Shweta S Zinzuwadia
- Department of Pharmacology, College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL, 34211, USA
| | - Yanelys Morera-Díaz
- Clinical Investigation and Biomedical Research Directions, Center for Genetic Engineering and Biotechnology, 11600, Havana, Cuba
| | - Devesh Tewari
- Department of Pharmacognosy and Phytochemistry, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, New Delhi, 110017, India.
| | - Anupam Bishayee
- Department of Pharmacology, College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL, 34211, USA.
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13
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Wang Z, Liu Y, Wang K, Ma L. Efficacy and safety of PD-1 and PD-L1 inhibitors in advanced colorectal cancer: a meta-analysis of randomized controlled trials. BMC Gastroenterol 2024; 24:461. [PMID: 39696009 DOI: 10.1186/s12876-024-03554-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2024] [Accepted: 12/09/2024] [Indexed: 12/20/2024] Open
Abstract
BACKGROUND PD-1 and PD-L1 inhibitors have emerged as promising therapies for advanced colorectal cancer (CRC), but their efficacy and safety profiles require further evaluation. This meta-analysis aims to assess the efficacy and safety of PD-1/PD-L1 inhibitors in this patient population. METHODS A systematic review and meta-analysis were conducted following PRISMA guidelines, with data sourced from PubMed, Embase, CENTRAL, Web of Science, and CNKI up to August 3, 2024. Nine randomized controlled trials (RCTs) involving 1680 patients were included. The primary outcomes were overall survival (OS), progression-free survival (PFS) and objective response rate (ORR), while safety was assessed through adverse events (AEs) and grade ≥ 3 AEs. Effect sizes were calculated using mean differences (MD) and risk ratios (RR) with 95% confidence intervals (CIs). RESULTS Overall, the meta-analysis showed that PD-1/PD-L1 inhibitors did not significantly extend OS (MD = 0.86, 95% CI: -0.55, 2.27), but they significantly improved PFS (MD = 2.53, 95% CI: 0.92, 4.15). Additionally, PD-1/PD-L1 inhibitors did not significantly increase the ORR compared to controls (RR = 1.19, 95% CI: 0.99, 1.44). In terms of safety, PD-1/PD-L1 inhibitors did not significantly increase the incidence of overall AEs. Subgroup analysis further indicated that PD-1 inhibitors significantly improved OS (MD = 1.24, 95% CI: 0.20, 2.29) and PFS (MD = 6.27, 95% CI: 0.56, 11.97), while PD-L1 inhibitors did not have a significant impact on these outcomes. Additionally, PD-L1 inhibitors were associated with a higher risk of grade ≥ 3 AEs (RR = 1.29, 95% CI: 1.07, 1.57), a risk not observed with PD-1 inhibitors. CONCLUSION PD-1 inhibitors significantly improve PFS and OS in advanced CRC, making them a preferable option over PD-L1 inhibitors, which show limited efficacy and a higher risk of severe AEs. These findings support prioritizing PD-1 inhibitors in clinical practice for this patient group, while caution is warranted with PD-L1 inhibitors due to their safety concerns. TRIAL REGISTRATION PROSPERO (CRD42024611696).
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Affiliation(s)
- Zhenzi Wang
- Department of Clinical Laboratory, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
| | - Yuan Liu
- Department of Clinical Laboratory, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
| | - Kedi Wang
- Department of Clinical Laboratory, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
| | - Liyan Ma
- Department of Clinical Laboratory, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
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14
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Martins SA, Correia JDG. 99mTc(I)-Labeled His-Tagged Proteins: Impact in the Development of Novel Imaging Probes and in Drug Discovery. Chembiochem 2024; 25:e202400645. [PMID: 39158861 DOI: 10.1002/cbic.202400645] [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: 08/02/2024] [Accepted: 08/07/2024] [Indexed: 08/20/2024]
Abstract
Technetium-99 m (99mTc) remains the cornerstone of nuclear medicine for single photon emission computed tomography (SPECT) due to its widespread availability and chemical and physical features. Its multiple oxidation states allow for the design and production of radiopharmaceuticals with versatile properties, namely in terms of pharmacokinetic profile. 99mTc(V) is the most common oxidation state, but 99mTc(I) gained traction after the pioneering work of Alberto and colleagues, which resulted in the introduction of the organometallic core fac-[99mTc(CO)3(H2O)3]+. This core is readily available from [99mTcO4]- and displays three labile water molecules that can be easily swapped for ligands with different denticity and/or donor atoms in aqueous environment. This makes it possible to radiolabel small molecules as well as high molecular weight molecules, such as antibodies or other proteins, while assuring biological activity. Direct radiolabelling of those proteins with fac-[99mTc(CO)3]+ under mild conditions is accomplished through incorporation of a polyhistidine tag (His-tag), a commonly used tag for purification of recombinant proteins. This review aims to address the direct radiolabelling of His-tagged macromolecules with fac-[99mTc(CO)3]+ for development of molecular imaging agents and the impact of this technology in the discovery and development of imaging and/or therapeutic agents towards clinical application.
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Affiliation(s)
- Sofia A Martins
- Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, CTN, Estrada Nacional 10 (km 139,7), 2695-066, Bobadela LRS, Portugal
| | - João D G Correia
- Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, CTN, Estrada Nacional 10 (km 139,7), 2695-066, Bobadela LRS, Portugal
- Departamento de Engenharia e Ciências Nucleares, Instituto Superior Técnico, Universidade de Lisboa, CTN, Estrada Nacional 10 (km 139,7), 2695-066, Bobadela LRS, Portugal
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15
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Liu Y, Liu F, Zeng Y, Lin L, Yu H, Zhang S, Yang W. Hydrogel systems for spatiotemporal controlled delivery of immunomodulators: engineering the tumor immune microenvironment for enhanced cancer immunotherapy. Front Cell Dev Biol 2024; 12:1514595. [PMID: 39735340 PMCID: PMC11681625 DOI: 10.3389/fcell.2024.1514595] [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: 10/21/2024] [Accepted: 11/28/2024] [Indexed: 12/31/2024] Open
Abstract
Tumor immunotherapy, modulating innate and adaptive immunity, has become an important therapeutic strategy. However, the tumor immune microenvironment's (TIME) complexity and heterogeneity challenge tumor immunotherapy. Hydrogel is a hydrophilic three-dimensional (3D) mesh structure with good biocompatibility and drug release control, which is widely used in drug delivery, agriculture, industry, etc. Hydrogels loaded with immune cells, cytokines, immune checkpoint inhibitors, and anti-tumor drugs can achieve targeted delivery and ultimately activate the immune response in the TIME. In this review, we will summarize the components of the TIME and their immune effects, the emerging immunomodulatory agents, the characteristics and functions of hydrogels, and how hydrogels regulate innate and adaptive immune cells in the TIME.
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Affiliation(s)
- Yanting Liu
- Department of Oncology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan, China
| | - Fang Liu
- Department of Neurosurgery, Department of Urology, Medical Research Center, The Second Chengdu Hospital Affiliated to Chongqing Medical University, The Affiliated Hospital of Southwest Jiaotong University, The Third People’s Hospital of Chengdu, Chengdu, China
- College of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, China
| | - Yan Zeng
- West China School of Basic Medical Sciences and Forensic Medicine, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China
| | - Liangbin Lin
- Department of Neurosurgery, Department of Urology, Medical Research Center, The Second Chengdu Hospital Affiliated to Chongqing Medical University, The Affiliated Hospital of Southwest Jiaotong University, The Third People’s Hospital of Chengdu, Chengdu, China
- Obesity and Metabolism Medicine-Engineering Integration Laboratory, Department of General Surgery, The Third People's Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, Chengdu, China
- The Center of Gastrointestinal and Minimally Invasive Surgery, Department of General Surgery, The Third People's Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, Chengdu, China
| | - Hui Yu
- Department of Neurosurgery, Department of Urology, Medical Research Center, The Second Chengdu Hospital Affiliated to Chongqing Medical University, The Affiliated Hospital of Southwest Jiaotong University, The Third People’s Hospital of Chengdu, Chengdu, China
| | - Sunfu Zhang
- Department of Neurosurgery, Department of Urology, Medical Research Center, The Second Chengdu Hospital Affiliated to Chongqing Medical University, The Affiliated Hospital of Southwest Jiaotong University, The Third People’s Hospital of Chengdu, Chengdu, China
| | - Wenyong Yang
- Department of Oncology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan, China
- Department of Neurosurgery, Department of Urology, Medical Research Center, The Second Chengdu Hospital Affiliated to Chongqing Medical University, The Affiliated Hospital of Southwest Jiaotong University, The Third People’s Hospital of Chengdu, Chengdu, China
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16
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Lee J, Yoo JS, Kim JH, Lee DY, Yang K, Kim B, Choi JI, Jang JW, Choi JY, Yoon SK, Han JW, Sung PS. Prognostic significance of combined PD-L1 expression in malignant and infiltrating cells in hepatocellular carcinoma treated with atezolizumab and bevacizumab. Front Immunol 2024; 15:1506355. [PMID: 39720711 PMCID: PMC11666515 DOI: 10.3389/fimmu.2024.1506355] [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: 10/05/2024] [Accepted: 11/25/2024] [Indexed: 12/26/2024] Open
Abstract
Background Programmed death-ligand 1 (PD-L1) expression is abundant not only in malignant cells but also in infiltrating cells within the tumor microenvironment (TME) of hepatocellular carcinoma (HCC). This study explored the association between PD-L1 expression in TME and outcomes in HCC patients treated with atezolizumab plus bevacizumab (AB), emphasizing the implications of PD-L1 expression in both malignant and tumor-infiltrating cells. Methods This study included 72 patients with HCC who underwent percutaneous core needle liver biopsy before AB treatment between September 2020 and December 2023. PD-L1 expression on tumor tissues was assessed using the combined positive score (CPS) with cutoff values of 1 and 10, utilizing antibody clone 22C3 (Dako). Results The distribution of PD-L1 CPS included 24 patients with CPS <1, 33 patients with CPS 1-10, and 15 patients with CPS ≥10. Significant differences in overall survival (OS) were observed across the three groups, with CPS ≥10 showing the highest survival rates (p = 0.010). Patients with CPS ≥10 had better OS than those with CPS <10 (median OS 14.8 vs. 8.3 months, P = 0.046), and CPS ≥1 had better OS than CPS <1 (P = 0.021). For progression-free survival (mPFS), the CPS ≥10 group had the highest median PFS of 11.0 months among the three groups (P = 0.044). Objective response rates (ORR) were higher in the PD-L1 CPS ≥10 group than in the 1-10 and <1 group (53.3%, 27.3%, and 16.7%, respectively; P = .047). Multivariate analysis identified that PD-L1 expression ≥10 and ≥1 were associated with favorable outcomes regarding OS (hazard ratio [HR] 0.283, P = .027 and HR 0.303, P = .006, respectively). Conclusions Combined analysis of PD-L1 expression in malignant and tumor-infiltrating cells can be a promising biomarker for the prognosis of HCC patients treated with AB.
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MESH Headings
- Humans
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/mortality
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/metabolism
- Liver Neoplasms/drug therapy
- Liver Neoplasms/mortality
- Liver Neoplasms/immunology
- Liver Neoplasms/pathology
- Liver Neoplasms/metabolism
- Liver Neoplasms/diagnosis
- B7-H1 Antigen/metabolism
- Male
- Female
- Bevacizumab/therapeutic use
- Bevacizumab/administration & dosage
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antibodies, Monoclonal, Humanized/administration & dosage
- Middle Aged
- Aged
- Prognosis
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Tumor Microenvironment/immunology
- Lymphocytes, Tumor-Infiltrating/immunology
- Lymphocytes, Tumor-Infiltrating/metabolism
- Adult
- Biomarkers, Tumor/metabolism
- Treatment Outcome
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Affiliation(s)
- Jaejun Lee
- The Catholic University Liver Research Center, Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Republic of Korea, Seoul, Republic of Korea
- Division of Hepatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Republic of Korea, Seoul, Republic of Korea
| | - Jae-Sung Yoo
- School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Ji Hoon Kim
- The Catholic University Liver Research Center, Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Republic of Korea, Seoul, Republic of Korea
- Division of Hepatology, Department of Internal Medicine, Uijeongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Republic of Korea, Seoul, Republic of Korea
| | - Dong Yeup Lee
- Division of Hepatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Republic of Korea, Seoul, Republic of Korea
| | - Keungmo Yang
- The Catholic University Liver Research Center, Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Republic of Korea, Seoul, Republic of Korea
- Division of Hepatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Republic of Korea, Seoul, Republic of Korea
| | - Bohyun Kim
- Departmend of Radiology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Republc of Korea, Seoul, Republic of Korea
| | - Joon-Il Choi
- Departmend of Radiology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Republc of Korea, Seoul, Republic of Korea
| | - Jeong Won Jang
- The Catholic University Liver Research Center, Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Republic of Korea, Seoul, Republic of Korea
- Division of Hepatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Republic of Korea, Seoul, Republic of Korea
| | - Jong Young Choi
- The Catholic University Liver Research Center, Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Republic of Korea, Seoul, Republic of Korea
- Division of Hepatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Republic of Korea, Seoul, Republic of Korea
| | - Seung Kew Yoon
- The Catholic University Liver Research Center, Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Republic of Korea, Seoul, Republic of Korea
- Division of Hepatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Republic of Korea, Seoul, Republic of Korea
| | - Ji Won Han
- The Catholic University Liver Research Center, Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Republic of Korea, Seoul, Republic of Korea
- Division of Hepatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Republic of Korea, Seoul, Republic of Korea
| | - Pil Soo Sung
- The Catholic University Liver Research Center, Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Republic of Korea, Seoul, Republic of Korea
- Division of Hepatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Republic of Korea, Seoul, Republic of Korea
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Fertitta V, Varano B, Del Cornò M, Fortini P, Aureli A, Conti L. Akkermansia muciniphila- and Pathogenic Bacteria-Derived Endotoxins Differently Regulate Human Dendritic Cell Generation and γδ T Lymphocyte Activation. Biomolecules 2024; 14:1571. [PMID: 39766278 PMCID: PMC11673428 DOI: 10.3390/biom14121571] [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: 10/25/2024] [Revised: 11/29/2024] [Accepted: 12/06/2024] [Indexed: 01/11/2025] Open
Abstract
Lipopolysaccharide (LPS) is a potent endotoxin released at high concentrations in acute infections, causing massive host inflammatory response. Accumulating evidence indicates that dysbiosis-associated chronic low levels of circulating LPS can sustain a prolonged sterile low-grade inflammation that increases the risk of several non-communicable diseases. Interventions aimed at increasing the abundance of beneficial/probiotic bacteria, including Akkermansia muciniphila, result in reduced inflammation, favoring metabolic and immune health. Immunosuppression is a common feature in conditions of chronic inflammation, and dendritic cells (DCs) represent key targets given their ability to shift the balance toward immunity or tolerance. In this study, the effects of low concentrations of LPS from pathogenic (Escherichia coli and Salmonella enterica) and probiotic (Akkermansia muciniphila) bacterial species on human DC generation and functions were compared. We report that monocyte precursor priming with Escherichia coli and Salmonella enterica LPS forces the differentiation of PD-L1-expressing DCs, releasing high levels of IL-6 and IL-10, and impairs their capacity to drive full TCR-Vδ2 T cell activation. Conversely, comparable concentrations of Akkermansia muciniphila promoted the generation of DCs with preserved activating potential and immunostimulatory properties. These results shed light on potential mechanisms underlying the impact of low endotoxemia on disease risk and pathogenesis, and increase our understanding of the immunomodulatory effects of Akkermansia muciniphila.
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Affiliation(s)
- Veronica Fertitta
- Department of Environment and Health, Istituto Superiore di Sanità, 00161 Rome, Italy; (V.F.); (P.F.)
| | - Barbara Varano
- Center for Gender-Specific Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy; (B.V.); (M.D.C.)
| | - Manuela Del Cornò
- Center for Gender-Specific Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy; (B.V.); (M.D.C.)
| | - Paola Fortini
- Department of Environment and Health, Istituto Superiore di Sanità, 00161 Rome, Italy; (V.F.); (P.F.)
| | - Anna Aureli
- Institute of Translational Pharmacology, National Research Council, 67100 L’Aquila, Italy;
| | - Lucia Conti
- Center for Gender-Specific Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy; (B.V.); (M.D.C.)
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Zhang J, Zhao P, Xu R, Han L, Chen W, Zhang Y. Comparison of the efficacy and safety of perioperative immunochemotherapeutic strategies for locally advanced esophageal cancer: a systematic review and network meta-analysis. Front Immunol 2024; 15:1478377. [PMID: 39712027 PMCID: PMC11659204 DOI: 10.3389/fimmu.2024.1478377] [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: 08/09/2024] [Accepted: 11/20/2024] [Indexed: 12/24/2024] Open
Abstract
Background The aim of this network meta-analysis was to clarify the efficacy and safety of different immune checkpoint inhibitors (ICIs) in combination with chemotherapy in the neoadjuvant phase for the treatment of locally advanced esophageal cancer. Methods We searched PubMed, EMBASE, Web of Science, Cochrane Library, CNKI and WanFang databases from January 2000 until May 2024. The primary endpoints were pathological complete response (pCR), major pathological response (MPR), R0 resection rate, objective response rate (ORR), disease control rate (DCR), treatment-related adverse events(TRAEs) of any grade and TRAEs of grade 3 or higher. The Newcastle-Ottawa Scale (NOS) and the Cochrane Risk of Bias tool were used to evaluate risk of bias. To analyze the data, Review Manager 5.3 and Stata16.0 were applied. Results Fourteen eligible studies (six randomized controlled trials) and 8 retrospective cohort studies) enrolling 1139 patients were included for this network meta-analysis. All studies originated from China. For patients with locally advanced esophageal cancer, neoadjuvant immunochemotherapeutic strategies showed significant advantages over traditional neoadjuvant therapy in terms of pCR, MPR, ORR and DCR. Among the analyzed regimens, camrelizumab plus chemotherapy demonstrated the most pronounced improvements in pCR and MPR, while pembrolizumab plus chemotherapy achieved the best outcomes in terms of ORR and DCR. There were no significant differences observed among the various neoadjuvant treatment strategies regarding R0 resection rate, any grade TRAEs, or grade≥3 TRAEs. The most common TRAEs in the neoadjuvant chemotherapy plus immunotherapy group were myelosuppression and gastrointestinal damage, with most grade 3 or higher TRAEs being hematologic adverse events. The most frequent immune-related adverse events(irAEs) included rash (4.2-21.7%), thyroid dysfunction (hypothyroidism or hyperthyroidism, 6.3-17.4%), and pneumonia (4.2-6.3%), with the majority being mild to moderate (grade 1 or 2). Conclusions Neoadjuvant immunotherapy combined with chemotherapy regimens demonstrate relatively high efficacy and tolerable safety profiles. Among the evaluated regimens, the combination chemotherapy with camrelizumab had relatively high pCR and MPR, whereas the combination chemotherapy with pembrolizumab had relatively high ORR and DCR. There were no significant differences in safety among the various regimens. Our study suggests that evaluating the efficacy and safety of different ICIs may be helpful in clinical decision-making. Systematic review registration https://www.crd.york.ac.uk/prospero/, identifier CRD42024583548.
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Affiliation(s)
- Jiao Zhang
- Department of Pharmacy, Shaanxi Province Tumor Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Peixi Zhao
- Department of Pharmacy, Shaanxi Province Tumor Hospital of Xi’an Jiaotong University, Xi’an, China
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, China
| | - Rui Xu
- Department of Oncology, Shaanxi Province Tumor Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Le Han
- Department of Chest Surgery, Shaanxi Province Tumor Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Wenjuan Chen
- Department of Chest Surgery, Shaanxi Province Tumor Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Yili Zhang
- Department of Oncology, Shaanxi Province Tumor Hospital of Xi’an Jiaotong University, Xi’an, China
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Rana PS, Ignatz-Hoover JJ, Guo C, Mosley AL, Malek E, Federov Y, Adams DJ, Driscoll JJ. Immunoproteasome Activation Expands the MHC Class I Immunopeptidome, Unmasks Neoantigens, and Enhances T-cell Anti-Myeloma Activity. Mol Cancer Ther 2024; 23:1743-1760. [PMID: 39210605 PMCID: PMC11612626 DOI: 10.1158/1535-7163.mct-23-0931] [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: 12/29/2023] [Revised: 04/30/2024] [Accepted: 08/16/2024] [Indexed: 09/04/2024]
Abstract
Proteasomes generate antigenic peptides that are presented on the tumor surface to cytotoxic T-lymphocytes. Immunoproteasomes are highly specialized proteasome variants that are expressed at higher levels in antigen-presenting cells and contain replacements of the three constitutive proteasome catalytic subunits to generate peptides with a hydrophobic C-terminus that fit within the groove of MHC class I (MHC-I) molecules. A hallmark of cancer is the ability to evade immunosurveillance by disrupting the antigen presentation machinery and downregulating MHC-I antigen presentation. High-throughput screening was performed to identify compound A, a novel molecule that selectively increased immunoproteasome activity and expanded the number and diversity of MHC-I-bound peptides presented on multiple myeloma cells. Compound A increased the presentation of individual MHC-I-bound peptides by >100-fold and unmasked tumor-specific neoantigens on myeloma cells. Global proteomic integral stability assays determined that compound A binds to the proteasome structural subunit PSMA1 and promotes association of the proteasome activator PA28α/β (PSME1/PSME2) with immunoproteasomes. CRISPR/Cas9 silencing of PSMA1, PSME1, or PSME2 as well as treatment with immunoproteasome-specific suicide inhibitors abolished the effects of compound A on antigen presentation. Treatment of multiple myeloma cell lines and patient bone marrow-derived CD138+ cells with compound A increased the anti-myeloma activity of allogenic and autologous T cells. Compound A was well-tolerated in vivo and co-treatment with allogeneic T cells reduced the growth of myeloma xenotransplants in NOD/SCID gamma mice. Taken together, our results demonstrate the paradigm shifting impact of immunoproteasome activators to diversify the antigenic landscape, expand the immunopeptidome, potentiate T-cell-directed therapy, and reveal actionable neoantigens for personalized T-cell immunotherapy.
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Affiliation(s)
- Priyanka S. Rana
- Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, Ohio
- Division of Hematology and Oncology, Department of Medicine, Case Western Reserve University, Cleveland, Ohio
| | - James J. Ignatz-Hoover
- Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, Ohio
- Division of Hematology and Oncology, Department of Medicine, Case Western Reserve University, Cleveland, Ohio
| | - Chunna Guo
- Center for Proteome Analysis, Indiana University School of Medicine, Indianapolis, Indiana
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Amber L. Mosley
- Center for Proteome Analysis, Indiana University School of Medicine, Indianapolis, Indiana
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Ehsan Malek
- Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, Ohio
- Division of Hematology and Oncology, Department of Medicine, Case Western Reserve University, Cleveland, Ohio
- Adult Hematologic Malignancies and Stem Cell Transplant Section, Seidman Cancer Center, University Hospitals Cleveland Medical Center, Cleveland, Ohio
| | - Yuriy Federov
- Small Molecule Drug Discovery Core, Case Western Reserve University, Cleveland, Ohio
| | - Drew J. Adams
- Small Molecule Drug Discovery Core, Case Western Reserve University, Cleveland, Ohio
| | - James J. Driscoll
- Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, Ohio
- Division of Hematology and Oncology, Department of Medicine, Case Western Reserve University, Cleveland, Ohio
- Adult Hematologic Malignancies and Stem Cell Transplant Section, Seidman Cancer Center, University Hospitals Cleveland Medical Center, Cleveland, Ohio
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Zheng M, Zhou L, Huang Y, Zhang X, Yu Z, Yang C, Chen Y, Ying D, Wang H, Chen Z, Liu C, Tang Z, Wang S, Wang K, Yang K, Lin Y, Li T, Zheng Q, Zheng Z, Zhang J, Yu H, Li S, Gu Y, Xia N. Structural basis for the synergetic neutralization of hepatitis E virus by antibody-antibody interaction. Proc Natl Acad Sci U S A 2024; 121:e2408585121. [PMID: 39585981 PMCID: PMC11626150 DOI: 10.1073/pnas.2408585121] [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: 05/04/2024] [Accepted: 09/24/2024] [Indexed: 11/27/2024] Open
Abstract
Neutralizing antibodies (nAbs) play a crucial role in virology, antibody drug development, and vaccine research. In this study, we investigated the synergistic effect of two hepatitis E virus (HEV) nAbs, 8H3, and 8C11, which have exhibited enhanced neutralizing activity in a rhesus monkey model. We presented crystal structures of 8H3 Fab alone and a triple complex of 8C11 Fab and 8H3 Fab simultaneously binding to the HEV E2s protein (8C11:E2s:8H3). Through structural analysis, we identified critical binding sites and fully elucidated the binding footprints of nAb 8H3 in the 8C11:E2s:8H3 complex using site-directed mutagenesis, pinpointing Ile 529, Glu 549, Lys 554, and Ser 566 in the E2s domain, and K66H, S67H, D88H in the 8C11 heavy chain. Interestingly, the synergetic enhancement of 8C11 to 8H3 converted to an antagonistic effect when 8C11 bound to E2s with pretreatment of 8H3, indicating a unidirectional synergistic effect associated with the sequence of antibody involvement. We demonstrated this phenomenon through structural comparisons of E2s:8C11 vs. 8C11:E2s:8H3 crystal structures and molecular dynamics simulations, found that Ile 529 played a key role in the synergistic interplay between these two nAbs. The two-antibody combination showed a more potent antibody-imposed physical disruption mechanism and enhanced coneutralization in an authentic HEV-based cell model. Our study suggests a strategy for synergistic antibody cocktail design with antibody-antibody side-by-side interaction.
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Affiliation(s)
- Minghua Zheng
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, School of Life Sciences, Xiamen University, Xiamen361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, Xiamen University, Xiamen361102, China
| | - Lizhi Zhou
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, School of Life Sciences, Xiamen University, Xiamen361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, Xiamen University, Xiamen361102, China
| | - Yang Huang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, School of Life Sciences, Xiamen University, Xiamen361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, Xiamen University, Xiamen361102, China
| | - Xiao Zhang
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, Xiamen University, Xiamen361102, China
| | - Zihao Yu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, School of Life Sciences, Xiamen University, Xiamen361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, Xiamen University, Xiamen361102, China
| | - Chengyu Yang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, School of Life Sciences, Xiamen University, Xiamen361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, Xiamen University, Xiamen361102, China
| | - Yuanzhi Chen
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, School of Life Sciences, Xiamen University, Xiamen361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, Xiamen University, Xiamen361102, China
| | - Dong Ying
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, School of Life Sciences, Xiamen University, Xiamen361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, Xiamen University, Xiamen361102, China
| | - Hong Wang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, School of Life Sciences, Xiamen University, Xiamen361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, Xiamen University, Xiamen361102, China
| | - Zhenqin Chen
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, School of Life Sciences, Xiamen University, Xiamen361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, Xiamen University, Xiamen361102, China
| | - Chang Liu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, School of Life Sciences, Xiamen University, Xiamen361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, Xiamen University, Xiamen361102, China
| | - Zimin Tang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, School of Life Sciences, Xiamen University, Xiamen361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, Xiamen University, Xiamen361102, China
| | - Siling Wang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, School of Life Sciences, Xiamen University, Xiamen361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, Xiamen University, Xiamen361102, China
| | - Kaihang Wang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, School of Life Sciences, Xiamen University, Xiamen361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, Xiamen University, Xiamen361102, China
| | - Kaixiang Yang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, School of Life Sciences, Xiamen University, Xiamen361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, Xiamen University, Xiamen361102, China
| | - Yanqing Lin
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, School of Life Sciences, Xiamen University, Xiamen361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, Xiamen University, Xiamen361102, China
| | - Tingting Li
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, School of Life Sciences, Xiamen University, Xiamen361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, Xiamen University, Xiamen361102, China
| | - Qingbing Zheng
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, School of Life Sciences, Xiamen University, Xiamen361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, Xiamen University, Xiamen361102, China
| | - Zizheng Zheng
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, School of Life Sciences, Xiamen University, Xiamen361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, Xiamen University, Xiamen361102, China
| | - Jun Zhang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, School of Life Sciences, Xiamen University, Xiamen361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, Xiamen University, Xiamen361102, China
| | - Hai Yu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, School of Life Sciences, Xiamen University, Xiamen361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, Xiamen University, Xiamen361102, China
| | - Shaowei Li
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, School of Life Sciences, Xiamen University, Xiamen361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, Xiamen University, Xiamen361102, China
| | - Ying Gu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, School of Life Sciences, Xiamen University, Xiamen361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, Xiamen University, Xiamen361102, China
| | - Ningshao Xia
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, School of Life Sciences, Xiamen University, Xiamen361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, Xiamen University, Xiamen361102, China
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Kouba S, Demaurex N. S-acylation of Ca 2+ transport proteins in cancer. Chronic Dis Transl Med 2024; 10:263-280. [PMID: 39429488 PMCID: PMC11483607 DOI: 10.1002/cdt3.146] [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: 05/17/2024] [Revised: 07/03/2024] [Accepted: 07/11/2024] [Indexed: 10/22/2024] Open
Abstract
Alterations in cellular calcium (Ca2+) signals have been causally associated with the development and progression of human cancers. Cellular Ca2+ signals are generated by channels, pumps, and exchangers that move Ca2+ ions across membranes and are decoded by effector proteins in the cytosol or in organelles. S-acylation, the reversible addition of 16-carbon fatty acids to proteins, modulates the activity of Ca2+ transporters by altering their affinity for lipids, and enzymes mediating this reversible post-translational modification have also been linked to several types of cancers. Here, we compile studies reporting an association between Ca2+ transporters or S-acylation enzymes with specific cancers, as well as studies reporting or predicting the S-acylation of Ca2+ transporters. We then discuss the potential role of S-acylation in the oncogenic potential of a subset of Ca2+ transport proteins involved in cancer.
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Affiliation(s)
- Sana Kouba
- Department of Cell Physiology and MetabolismCentre Médical Universitaire, University of GenevaGenevaSwitzerland
| | - Nicolas Demaurex
- Department of Cell Physiology and MetabolismCentre Médical Universitaire, University of GenevaGenevaSwitzerland
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Shi X, Cheng X, Jiang A, Shi W, Zhu L, Mou W, Glaviano A, Liu Z, Cheng Q, Lin A, Wang L, Luo P. Immune Checkpoints in B Cells: Unlocking New Potentials in Cancer Treatment. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2403423. [PMID: 39509319 DOI: 10.1002/advs.202403423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 08/26/2024] [Indexed: 11/15/2024]
Abstract
B cells are crucial component of humoral immunity, and their role in the tumor immune microenvironment (TME) has garnered significant attention in recent years. These cells hold great potential and application prospects in the field of tumor immunotherapy. Research has demonstrated that the TME can remodel various B cell functions, including proliferation, differentiation, antigen presentation, and antibody production, thereby invalidating the anti-tumor effects of B cells. Concurrently, numerous immune checkpoints (ICs) on the surface of B cells are upregulated. Aberrant B-cell IC signals not only impair the function of B cells themselves, but also modulate the tumor-killing effects of other immune cells, ultimately fostering an immunosuppressive TME and facilitating tumor immune escape. Blocking ICs on B cells is beneficial for reversing the immunosuppressive TME and restoring anti-tumor immune responses. In this paper, the intricate connection between B-cell ICs and the TME is delved into, emphasizing the critical role of targeting B-cell ICs in anti-tumor immunity, which may provide valuable insights for the future development of tumor immunotherapy based on B cells.
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Affiliation(s)
- Xiaoye Shi
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, 510282, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Xiangshu Cheng
- College of Bioinformatics Science and Technology, Harbin Medical University, 157 Baojian Road. Nangang District, Harbin, Heilongiiang, 150076, China
| | - Aimin Jiang
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, 200433, China
| | - Wenjie Shi
- Molecular and Experimental Surgery, University Clinic for General-, Visceral-, Vascular- and Trans-Plantation Surgery, Medical Faculty University Hospital Magdeburg, Otto-von Guericke University, 39120, Magdeburg, Germany
| | - Lingxuan Zhu
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, 510282, China
| | - Weiming Mou
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, 510282, China
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Antonino Glaviano
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Palermo, 90123, Italy
| | - Zaoqu Liu
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Quan Cheng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Anqi Lin
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, 510282, China
| | - Linhui Wang
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, 200433, China
| | - Peng Luo
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, 510282, China
- Cancer Centre and Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau SAR, 999078, China
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23
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Xian Y, Ye J, Tang Y, Zhang N, Peng C, Huang W, He G. Deubiquitinases as novel therapeutic targets for diseases. MedComm (Beijing) 2024; 5:e70036. [PMID: 39678489 PMCID: PMC11645450 DOI: 10.1002/mco2.70036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 11/24/2024] [Accepted: 11/26/2024] [Indexed: 12/17/2024] Open
Abstract
Deubiquitinating enzymes (DUBs) regulate substrate ubiquitination by removing ubiquitin or cleaving within ubiquitin chains, thereby maintaining cellular homeostasis. Approximately 100 DUBs in humans counteract E3 ubiquitin ligases, finely balancing ubiquitination and deubiquitination processes to maintain cellular proteostasis and respond to various stimuli and stresses. Given their role in modulating ubiquitination levels of various substrates, DUBs are increasingly linked to human health and disease. Here, we review the DUB family, highlighting their distinctive structural characteristics and chain-type specificities. We show that DUB family members regulate key signaling pathways, such as NF-κB, PI3K/Akt/mTOR, and MAPK, and play crucial roles in tumorigenesis and other diseases (neurodegenerative disorders, cardiovascular diseases, inflammatory disorders, and developmental diseases), making them promising therapeutic targets Our review also discusses the challenges in developing DUB inhibitors and underscores the critical role of the DUBs in cellular signaling and cancer. This comprehensive analysis enhances our understanding of the complex biological functions of the DUBs and underscores their therapeutic potential.
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Affiliation(s)
- Yali Xian
- Department of Dermatology & VenerologyState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengduChina
| | - Jing Ye
- Department of Dermatology & VenerologyState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengduChina
| | - Yu Tang
- Department of Dermatology & VenerologyState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengduChina
| | - Nan Zhang
- State Key Laboratory of Southwestern Chinese Medicine ResourcesSchool of PharmacyChengdu University of Traditional Chinese MedicineChengduChina
| | - Cheng Peng
- State Key Laboratory of Southwestern Chinese Medicine ResourcesSchool of PharmacyChengdu University of Traditional Chinese MedicineChengduChina
| | - Wei Huang
- State Key Laboratory of Southwestern Chinese Medicine ResourcesSchool of PharmacyChengdu University of Traditional Chinese MedicineChengduChina
| | - Gu He
- Department of Dermatology & VenerologyState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengduChina
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24
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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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25
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Rico-Méndez MA, Ayala-Madrigal MDLL, González-Mercado A, Gutiérrez-Angulo M, Ramírez de Arellano Sánchez JA, Beltrán-Ontiveros SA, Contreras-Haro B, Gutiérrez-Hurtado IA, Moreno-Ortiz JM. Microsatellite Instability in Urine: Breakthrough Method for Bladder Cancer Identification. Biomedicines 2024; 12:2726. [PMID: 39767633 PMCID: PMC11727160 DOI: 10.3390/biomedicines12122726] [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: 11/07/2024] [Revised: 11/21/2024] [Accepted: 11/26/2024] [Indexed: 01/16/2025] Open
Abstract
Bladder cancer (BC) is the most common neoplasm of the urinary system and ranks tenth in global cancer incidence. Due to its high recurrence rate and the need for continuous monitoring, it is the cancer with the highest cost per patient. Cystoscopy is the traditional method for its detection and surveillance; however, this is an invasive technique, while non-invasive methods, such as cytology, have a limited sensitivity. For this reason, new non-invasive strategies have emerged, analyzing useful markers for BC detection from urine samples. The identification of tumor markers is essential for early cancer detection and treatment. Urine analysis offers a non-invasive method to identify these markers. Microsatellite instability (MSI) has been proposed as a promising marker for tumor cell detection and guided targeted therapies. Therefore, this review aims to explore the evidence supporting the identification of MSI in exfoliated bladder tumor cells (EBTCs) in the urine, emphasizing its potential as a non-invasive and clinically effective alternative for tumor identification. Furthermore, establishing clinical guidelines is crucial for standardizing its application in oncological screening and validating its clinical utility.
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Affiliation(s)
- Manuel Alejandro Rico-Méndez
- Doctorado en Genética Humana, Instituto de Genética Humana “Dr. Enrique Corona Rivera”, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (M.A.R.-M.); (M.d.l.L.A.-M.); (A.G.-M.)
| | - María de la Luz Ayala-Madrigal
- Doctorado en Genética Humana, Instituto de Genética Humana “Dr. Enrique Corona Rivera”, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (M.A.R.-M.); (M.d.l.L.A.-M.); (A.G.-M.)
| | - Anahí González-Mercado
- Doctorado en Genética Humana, Instituto de Genética Humana “Dr. Enrique Corona Rivera”, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (M.A.R.-M.); (M.d.l.L.A.-M.); (A.G.-M.)
| | - Melva Gutiérrez-Angulo
- Departamento de Ciencias de la Salud, Centro Universitario de los Altos, Universidad de Guadalajara, Tepatitlán de Morelos 47600, Jalisco, Mexico;
| | - Jorge Adrián Ramírez de Arellano Sánchez
- Instituto de Investigación en Ciencias Biomédicas, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico;
| | - Saul Armando Beltrán-Ontiveros
- Centrode Investigación y Docencia en Ciencias de la Salud, Universidad Autónoma de Sinaloa, Culiacán Rosales 80030, Sinaloa, Mexico;
| | - Betsabe Contreras-Haro
- Unidad de Investigación Biomédica 02, Unidades Médicas de Alta Especialidad, Hospital de Especialidades, Centro Médico Nacional de Occidente, Instituto Mexicano del Seguro Social, Guadalajara 44329, Jalisco, Mexico;
| | - Itzae Adonai Gutiérrez-Hurtado
- Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
| | - José Miguel Moreno-Ortiz
- Doctorado en Genética Humana, Instituto de Genética Humana “Dr. Enrique Corona Rivera”, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (M.A.R.-M.); (M.d.l.L.A.-M.); (A.G.-M.)
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26
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Albertí-Valls M, Olave S, Olomí A, Macià A, Eritja N. Advances in Immunotherapy for Endometrial Cancer: Insights into MMR Status and Tumor Microenvironment. Cancers (Basel) 2024; 16:3918. [PMID: 39682106 DOI: 10.3390/cancers16233918] [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: 10/30/2024] [Revised: 11/18/2024] [Accepted: 11/19/2024] [Indexed: 12/18/2024] Open
Abstract
Endometrial cancer is one of the most common gynecological malignancies, and while early-stage cases are highly treatable, recurrent or advanced EC remains challenging to manage. Immunotherapy, particularly immune checkpoint inhibitors, has revolutionized treatment approaches in oncology, and its application in EC has shown promising results. Key to immunotherapy efficacy in EC is the tumor's mismatch repair status, with MMR-deficient tumors demonstrating a higher tumor mutational burden and increased PD-L1 expression, making them more susceptible to immune checkpoint inhibitors (ICIs) such as pembrolizumab, durvalumab, and dostarlimab. However, not all mismatch repair-deficient (MMRd) tumors respond to ICIs, particularly those with a "cold" tumor microenvironment (TME) characterized by poor immune infiltration. In contrast, some MMR-proficient tumors with a "hot" TME respond well to ICIs, underscoring the complex interplay between MMR status, tumor mutational burden (TMB), and TME. To overcome resistance in cold tumors, novel therapies, including Chimeric Antigen Receptor (CAR) T cells and tumor-infiltrating lymphocytes are being explored, offering targeted immune-based strategies to enhance treatment efficacy. This review discusses the current understanding of immunotherapy in EC, emphasizing the prognostic and therapeutic implications of MMR status, TME composition, and emerging cell-based therapies.
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Affiliation(s)
- Manel Albertí-Valls
- Oncologic Pathology Group, Biomedical Research Institute of Lleida (IRBLleida), University of Lleida (UdL), Av. Rovira Roure 80, 25198 Lleida, Spain
| | - Sara Olave
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
| | - Anna Olomí
- Developmental and Oncogenic Signaling, Biomedical Research Institute of Lleida (IRBLleida), University of Lleida (UdL), Av. Rovira Roure 80, 25198 Lleida, Spain
| | - Anna Macià
- Oncologic Pathology Group, Biomedical Research Institute of Lleida (IRBLleida), University of Lleida (UdL), Av. Rovira Roure 80, 25198 Lleida, Spain
| | - Núria Eritja
- Oncologic Pathology Group, Biomedical Research Institute of Lleida (IRBLleida), University of Lleida (UdL), Av. Rovira Roure 80, 25198 Lleida, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
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27
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Ahmadi SE, Rahimian E, Rahimi S, Zarandi B, Bahraini M, Soleymani M, Safdari SM, Shabannezhad A, Jaafari N, Safa M. From regulation to deregulation of p53 in hematologic malignancies: implications for diagnosis, prognosis and therapy. Biomark Res 2024; 12:137. [PMID: 39538363 PMCID: PMC11565275 DOI: 10.1186/s40364-024-00676-9] [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: 07/16/2024] [Accepted: 10/22/2024] [Indexed: 11/16/2024] Open
Abstract
The p53 protein, encoded by the TP53 gene, serves as a critical tumor suppressor, playing a vital role in maintaining genomic stability and regulating cellular responses to stress. Dysregulation of p53 is frequently observed in hematological malignancies, significantly impacting disease progression and patient outcomes. This review aims to examine the regulatory mechanisms of p53, the implications of TP53 mutations in various hematological cancers, and emerging therapeutic strategies targeting p53. We conducted a comprehensive literature review to synthesize recent findings related to p53's multifaceted role in hematologic cancers, focusing on its regulatory pathways and therapeutic potential. TP53 mutations in hematological malignancies often lead to treatment resistance and poor prognosis. Current therapeutic strategies, including p53 reactivation and gene therapy, show promise in improving treatment outcomes. Understanding the intricacies of p53 regulation and the consequences of its mutations is essential for developing effective diagnostic and therapeutic strategies in hematological malignancies, ultimately enhancing patient care and survival.
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Affiliation(s)
- Seyed Esmaeil Ahmadi
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Elahe Rahimian
- Department of Medical Translational Oncology, National Center for Tumor Diseases (NCT) Dresden, Dresden, Germany
| | - Samira Rahimi
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Bahman Zarandi
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mehran Bahraini
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Maral Soleymani
- Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Seyed Mehrab Safdari
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ashkan Shabannezhad
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Niloofar Jaafari
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Majid Safa
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran.
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28
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Ali SH, Ali H, Aziz MA. Computational identification of PDL1 inhibitors and their cytotoxic effects with silver and gold nanoparticles. Sci Rep 2024; 14:26610. [PMID: 39496756 PMCID: PMC11535480 DOI: 10.1038/s41598-024-77868-8] [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: 07/08/2024] [Accepted: 10/25/2024] [Indexed: 11/06/2024] Open
Abstract
Immunotherapy is a promising treatment for cancer that aims to boost the immune system's response to cancer cells. This can be achieved by blocking Programmed cell death protein 1/Programmed death-ligand 1 (PD1/PDL1), which activates T cells. In this work, the aim was to find high-affinity drugs against PDL1 using computational tools and conjugate nanoparticles with them. The cytotoxic activity of the nanoparticle conjugated drugs was then tested. The screening of 100,000 drugs from the ZINC database and FDA-approved drugs was done computationally. The physicochemical properties and toxicity of the drugs were analyzed using SwissADME and ProTox-II, respectively. Silver nanoparticles (AgNPs) and gold nanoparticles (AuNPs) were synthesized using extracts of Catharanthus roseus flowers and Juglans regia shells, respectively. The characterization of AgNPs and AuNPs was performed using UV-Vis spectroscopy, X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR). Their conjugation with the drugs Irinotecan, Imatinib, and Methotrexate was also confirmed using UV-Vis, FTIR, and Dynamic light scattering (DLS). The top screened drugs were ZINC1098661 and 3 FDA-approved drugs (Irinotecan, Imatinib, and Methotrexate). Docking studies revealed that Irinotecan had the highest binding affinity towards PDL1 when conjugated with silver nanoparticles (AgNPs) and gold nanoparticles (AuNPs). The Irinotecan-PDL1 complex was confirmed as the most stable through molecular dynamics simulations. The result of the methylthiazol tetrazolium (MTT) assay showed that conjugated AgNPs and AuNPs with Irinotecan had a higher toxic effect on the A549 cancer cell line than AgNPs and AuNPs conjugated with Imatinib. This study provides a promising avenue for further investigation and development of nanoparticle-drug conjugates as a potential cancer immunotherapy strategy.
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Affiliation(s)
- Syed Hammad Ali
- Interdisciplinary Nanotechnology Centre, Aligarh Muslim University, Aligarh, UP, 202002, India
| | - Hiba Ali
- Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, India
| | - Mohd Azhar Aziz
- Interdisciplinary Nanotechnology Centre, Aligarh Muslim University, Aligarh, UP, 202002, India.
- Cancer Nanomedicine Consortium, Aligarh Muslim University, Aligarh, India.
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29
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Dev ID, Puranik AD, Singh B, Prasad V. Current and Future Perspectives of PDL1 PET and SPECT Imaging. Semin Nucl Med 2024; 54:966-975. [PMID: 39510854 DOI: 10.1053/j.semnuclmed.2024.09.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Accepted: 09/20/2024] [Indexed: 11/15/2024]
Abstract
Programmed Death 1 (PD1) and Programmed Death Ligand (PDL1) play a crucial role in tumor microenvironment by helping cancer cells evade innate immunity. Numerous inhibitor anticancer drugs targeting this interplay have been used in clinical practice and many more are in preclinical stage. These drugs have shown promising results in achieving good response and long-term clinical benefit, is routinely performed to identify patients who may benefit. However, there are major challenges associated with these immunohistochemistry tests which have opened the space for noninvasive imaging modalities using PD1 and PDL1 inhibitors labeled with either PET or SPECT radionuclides. These radiopharmaceuticals, although primarily developed for the field of immunotherapy, have great potential in expanding and optimizing the combination of radiopharmaceutical therapies with PD1-PDL1 targeting anticancer drugs. This review elaborates currently available PET and SPECT radiopharmaceuticals targeting PD1-PDL1 axis. It also explores the potential future role of newer targets which are being developed and tested in various preclinical studies.
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Affiliation(s)
- Indraja D Dev
- Assistant Professor, Department of Nuclear Medicine and Molecular Imaging, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India
| | - Ameya D Puranik
- Professor, Department of Nuclear Medicine and Molecular Imaging, Tata Memorial Hospital, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India
| | - Baljinder Singh
- Professor, Department of Nuclear Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Vikas Prasad
- Director of Clinical Theranostics, Division of Nuclear Medicine, Mallinckrodt Institute of Radiology, Washington, WA.
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30
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Xu C. CRISPR/Cas9-mediated knockout strategies for enhancing immunotherapy in breast cancer. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:8561-8601. [PMID: 38907847 DOI: 10.1007/s00210-024-03208-2] [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: 12/28/2023] [Accepted: 05/31/2024] [Indexed: 06/24/2024]
Abstract
Breast cancer, a prevalent disease with significant mortality rates, often presents treatment challenges due to its complex genetic makeup. This review explores the potential of combining Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) gene knockout strategies with immunotherapeutic approaches to enhance breast cancer treatment. The CRISPR/Cas9 system, renowned for its precision in inducing genetic alterations, can target and eliminate specific cancer cells, thereby minimizing off-target effects. Concurrently, immunotherapy, which leverages the immune system's power to combat cancer, has shown promise in treating breast cancer. By integrating these two strategies, we can potentially augment the effectiveness of immunotherapies by knocking out genes that enable cancer cells to evade the immune system. However, safety considerations, such as off-target effects and immune responses, necessitate careful evaluation. Current research endeavors aim to optimize these strategies and ascertain the most effective methods to stimulate the immune response. This review provides novel insights into the integration of CRISPR/Cas9-mediated knockout strategies and immunotherapy, a promising avenue that could revolutionize breast cancer treatment as our understanding of the immune system's interplay with cancer deepens.
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Affiliation(s)
- Chenchen Xu
- Department of Gynecology and Obstetrics, Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, 213000, China.
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31
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Cao WH, Zhang YQ, Li XX, Zhang ZY, Li MH. Advances in immunotherapy for hepatitis B virus associated hepatocellular carcinoma patients. World J Hepatol 2024; 16:1158-1168. [PMID: 39474576 PMCID: PMC11514615 DOI: 10.4254/wjh.v16.i10.1158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 08/28/2024] [Accepted: 09/19/2024] [Indexed: 10/21/2024] Open
Abstract
Hepatitis B virus (HBV) infection plays an important role in the occurrence and development of hepatocellular carcinoma (HCC), and the rate of HBV infection in liver cancer patients in China is as high as 92.05%. Due to long-term exposure to chronic antigens from the gut, the liver needs to maintain a certain level of immune tolerance, both to avoid severe inflammation caused by non-pathogenic antigens and to maintain the possibility of rapid and violent responses to infection and tumors. Therefore, HBV infection interacts with the tumor microenvironment (TME) through a highly complex and intertwined signaling pathway, which results in a special TME in HCC. Due to changes in the TME, tumor cells can evade immune surveillance by inhibiting tumor-specific T cell function through cytotoxic T-lymphocy-associated protein-4 (CTLA-4) and programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1). Interferons, as a class of immune factors with strong biological activity, can improve the TME of HBV-HCC through various pathways. In recent years, the systematic treatment of HCC has gradually come out of the dilemma. In addition to the continuous emergence of new multi-target anti-vascular tyrosine kinase inhibitor drugs, immune checkpoint inhibitors have opened up a new avenue for the systematic treatment of HCC. At present, immunotherapy based on PD-1/L1 inhibitors has gradually become a new direction of systematic treatment for HCC, and the disease characteristics of patients included in global clinical studies are different from those of Chinese patients. Therefore, whether a group of HCC patients with HBV background and poor prognosis in China can also benefit from immunotherapy is an issue of wide concern. This review aims to elucidate the advances of immunotherapy for HBV related HCC patients with regard to: (1) Immunotherapy based on interferons; (2) Immunotherapy based on PD-1/L1 inhibitors; (3) Immunotherapy based on CTLA4 inhibitors; (4) Adoptive cell transfer; (5) Combination immunotherapy strategy; and (6) Shortcomings of immunotherapy.
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Affiliation(s)
- Wei-Hua Cao
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Ya-Qin Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Xin-Xin Li
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Zi-Yu Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Ming-Hui Li
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Peking University Ditan Teaching Hospital, Beijing 100015, China
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32
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Cao WH, Zhang YQ, Li XX, Zhang ZY, Li MH. Advances in immunotherapy for hepatitis B virus associated hepatocellular carcinoma patients. World J Hepatol 2024; 16:1338-1348. [DOI: 10.4254/wjh.v16.i10.1338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 08/28/2024] [Accepted: 09/19/2024] [Indexed: 11/22/2024] Open
Abstract
Hepatitis B virus (HBV) infection plays an important role in the occurrence and development of hepatocellular carcinoma (HCC), and the rate of HBV infection in liver cancer patients in China is as high as 92.05%. Due to long-term exposure to chronic antigens from the gut, the liver needs to maintain a certain level of immune tolerance, both to avoid severe inflammation caused by non-pathogenic antigens and to maintain the possibility of rapid and violent responses to infection and tumors. Therefore, HBV infection interacts with the tumor microenvironment (TME) through a highly complex and intertwined signaling pathway, which results in a special TME in HCC. Due to changes in the TME, tumor cells can evade immune surveillance by inhibiting tumor-specific T cell function through cytotoxic T-lymphocy-associated protein-4 (CTLA-4) and programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1). Interferons, as a class of immune factors with strong biological activity, can improve the TME of HBV-HCC through various pathways. In recent years, the systematic treatment of HCC has gradually come out of the dilemma. In addition to the continuous emergence of new multi-target anti-vascular tyrosine kinase inhibitor drugs, immune checkpoint inhibitors have opened up a new avenue for the systematic treatment of HCC. At present, immunotherapy based on PD-1/L1 inhibitors has gradually become a new direction of systematic treatment for HCC, and the disease characteristics of patients included in global clinical studies are different from those of Chinese patients. Therefore, whether a group of HCC patients with HBV background and poor prognosis in China can also benefit from immunotherapy is an issue of wide concern. This review aims to elucidate the advances of immunotherapy for HBV related HCC patients with regard to: (1) Immunotherapy based on interferons; (2) Immunotherapy based on PD-1/L1 inhibitors; (3) Immunotherapy based on CTLA4 inhibitors; (4) Adoptive cell transfer; (5) Combination immunotherapy strategy; and (6) Shortcomings of immunotherapy.
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Affiliation(s)
- Wei-Hua Cao
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Ya-Qin Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Xin-Xin Li
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Zi-Yu Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Ming-Hui Li
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Peking University Ditan Teaching Hospital, Beijing 100015, China
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33
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Liao K, Cheng J, Hu Y, Zhang B, Huang P, Liu J, Zhang W, Hu H, Bai X, Qian Y, Guo D, Ai K, Zhu Y, Huang L. Evaluation of the safety of PD-1/PD-L1 inhibitors for immunotherapy in patients with malignant tumors after COVID-19 infection: A single-center cohort study. Cancer Med 2024; 13:e70202. [PMID: 39377592 PMCID: PMC11459677 DOI: 10.1002/cam4.70202] [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: 03/12/2024] [Revised: 08/08/2024] [Accepted: 08/26/2024] [Indexed: 10/09/2024] Open
Abstract
INTRODUCTION An increasing body of evidence suggests a close association between COVID-19 infection and the safety of PD-1/PD-L1 inhibitor therapy in cancer patients. However, the available data concerning these impacts remain limited and occasionally contradictory. MATERIAL AND METHODS We conducted a retrospective analysis of cancer patients who received PD-1/PD-L1 inhibitor therapy at the same institution from November 2022 to May 2023. After excluding patients with missing information, a total of 224 cases were included. In our study, immune-related adverse events (irAEs) that occurred during the hospitalization of patients were included in the analysis. Further analysis of inter-subgroup differences was conducted following a 1:2 propensity score matching. Statistical analyses were performed using the Fisher's exact, chi-squared, and Mann-Whitney U-tests. RESULT The results showed that no statistically significant differences between the two subgroups in the incidence of irAEs, changes in immune function before and after using PD-1/PD-L1 inhibitors, and alterations in hepatic and renal function (p > 0.05). CONCLUSION Our findings suggest that infection with COVID-19 does not significantly impact the safety of PD-1/PD-L1 inhibitors in cancer patients. Most cancer patients used PD-1/PD-L1 inhibitors during COVID-19 infection (asymptomatic or mild infection) did not experience exacerbation of their underlying condition, nor did they exhibit a substantial increase in toxic side effects.
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Affiliation(s)
- Kaili Liao
- Department of Clinical Laboratory, the 2nd Affiliated Hospital, Jiangxi Medical CollegeNanchang UniversityNanchangChina
| | - Jinting Cheng
- School of Public Health, Jiangxi Medical CollegeNanchang UniversityNanchangChina
| | - Yujie Hu
- The 1st Clinical Medical College, Jiangxi Medical CollegeNanchang UniversityNanchangChina
| | - Beining Zhang
- Queen Mary College, Jiangxi Medical College, Nanchang UniversityNanchangChina
| | - Peng Huang
- Department of Oncology, the 2nd Affiliated Hospital, Jiangxi Medical CollegeNanchang UniversityNanchangChina
| | - Jie Liu
- School of Public Health, Jiangxi Medical CollegeNanchang UniversityNanchangChina
| | - Wenyige Zhang
- Queen Mary College, Jiangxi Medical College, Nanchang UniversityNanchangChina
| | - Huan Hu
- School of Public Health, Jiangxi Medical CollegeNanchang UniversityNanchangChina
| | - Xinyi Bai
- School of Public Health, Jiangxi Medical CollegeNanchang UniversityNanchangChina
| | - Yihui Qian
- The 2nd Clinical Medical College, Jiangxi Medical CollegeNanchang UniversityNanchangChina
| | - Daixin Guo
- School of Public Health, Jiangxi Medical CollegeNanchang UniversityNanchangChina
| | - Kun Ai
- Queen Mary College, Jiangxi Medical College, Nanchang UniversityNanchangChina
| | - Yuchen Zhu
- The 1st Clinical Medical College, Jiangxi Medical CollegeNanchang UniversityNanchangChina
| | - Long Huang
- Department of Oncology, the 2nd Affiliated Hospital, Jiangxi Medical CollegeNanchang UniversityNanchangChina
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Vogiatzi I, Lama LM, Lehmann A, Rossignoli F, Gettemans J, Shah K. Allogeneic stem cells engineered to release interferon β and scFv-PD1 target glioblastoma and alter the tumor microenvironment. Cytotherapy 2024; 26:1217-1226. [PMID: 38852095 PMCID: PMC11427148 DOI: 10.1016/j.jcyt.2024.05.012] [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: 03/14/2024] [Revised: 05/09/2024] [Accepted: 05/13/2024] [Indexed: 06/10/2024]
Abstract
Highly malignant brain tumors, glioblastomas (GBM), are immunosuppressive, thereby limiting current promising immunotherapeutic approaches. In this study, we created interferon receptor 1 knockout allogeneic mesenchymal stem cells (MSC) to secrete dual-function pro-apoptotic and immunomodulatory interferon (IFN) β (MSCKO-IFNβ) using a single lentiviral vector CRISPR/Cas9 system. We show that MSCKO-IFNβ induces apoptosis in GBM cells and upregulates the cell surface expression of programmed death ligand-1 in tumor cells. Next, we engineered MSCKO to release a secretable single-chain variable fragment (scFv) to block programmed death (PD)-1 and show the ability of MSCKO-scFv-PD1 to enhance T-cell activation and T-cell-mediated tumor cell killing. To simultaneously express both immune modulators, we engineered MSCKO-IFNβ to co-express scFv-PD1 (MSCKO-IFNβ-scFv-PD1) and show the expression of both IFNβ and scFv-PD1 in vitro leads to T-cell activation and lowers the viability of tumor cells. Furthermore, to mimic the clinical scenario of GBM tumor resection and subsequent treatment, we show that synthetic extracellular matrix (sECM) encapsulated MSCKO-IFNβ-scFv-PD1 treatment of resected tumors results in the increase of CD4+ and CD8+ T cells, mature conventional dendritic cells type II and activation of microglia as compared to the control treatment group. Overall, these results reveal the ability of MSCKO-IFNβ-scFv-PD1 to shape the tumor microenvironment and enhance therapeutic outcomes in GBM.
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Affiliation(s)
- Ioulia Vogiatzi
- Center for Stem Cell and Translational Immunotherapy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Biomolecular Medicine, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Lucia Moreno Lama
- Center for Stem Cell and Translational Immunotherapy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Amelia Lehmann
- Center for Stem Cell and Translational Immunotherapy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Filippo Rossignoli
- Center for Stem Cell and Translational Immunotherapy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Jan Gettemans
- Department of Biomolecular Medicine, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Khalid Shah
- Center for Stem Cell and Translational Immunotherapy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA.
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35
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Shi YY, Fan G, Tan R, Li S, Sun HB, Li R, Yang M, Gao S, Liu M, Dai MY. Treating ICB-resistant cancer by inhibiting PD-L1 via DHHC3 degradation induced by cell penetrating peptide-induced chimera conjugates. Cell Death Dis 2024; 15:701. [PMID: 39349454 PMCID: PMC11442653 DOI: 10.1038/s41419-024-07073-y] [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: 06/22/2024] [Revised: 09/04/2024] [Accepted: 09/12/2024] [Indexed: 10/02/2024]
Abstract
The current selection of ligands for both proteins of interest (POI) and E3 ubiquitin ligase significantly restricts the scope of targeted protein degradation (TPD) technologies. This study introduces cell-penetrating peptide-induced chimera conjugates (cp-PCCs) targeting the DHHC3 enzyme involved in PD-L1 palmitoylation. This approach disrupts PD-L1's immunosuppressive function, enhancing anti-tumor immunity. We developed cp-PCCs to degrade DHHC3, directly linking DHHC3-mediated PD-L1 palmitoylation to PD-L1 stability on tumor cells. Our research utilized both in vitro assays and in vivo experiments in immune checkpoint blockade-resistant mouse models. We focused on a CRBN-based cp-PCC named PCC16, which demonstrated a DC50 of 102 nmol for DHHC3 degradation and significantly reduced PD-L1 levels. In resistant models, PCC16 not only robustly downregulated PD-L1 but also exhibited substantial anti-tumor activity in vivo without significant toxicity. This outperformed traditional inhibitors, showcasing the potential of cp-PCC technology to bypass current PROTAC limitations. Our findings suggest that cp-PCCs offer a promising method for targeting PD-L1 through DHHC3 inhibition and support their continued exploration as a versatile tool in cancer immunotherapy, especially for tumors resistant to standard treatments.
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Affiliation(s)
- Yu-Ying Shi
- Department of Gynecological Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Gang Fan
- Department of Urology, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, China
| | - Ruirong Tan
- ChinaTranslational Chinese Medicine Key Laboratory of Sichuan Province, State Key Laboratory of Quality Evaluation of Traditional Chinese Medicine, Sichuan Institute for Translational Chinese Medicine, Sichuan Academy of Chinese Medicine Sciences, Chengdu, China
| | - Shan Li
- Department of Gynecological Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Hua-Bing Sun
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Department of Nuclear Medicine, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China
| | - Rui Li
- Department of Radiation Oncology, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, Chengdu, China
| | - Mengni Yang
- ChinaTranslational Chinese Medicine Key Laboratory of Sichuan Province, State Key Laboratory of Quality Evaluation of Traditional Chinese Medicine, Sichuan Institute for Translational Chinese Medicine, Sichuan Academy of Chinese Medicine Sciences, Chengdu, China
| | - Shanshan Gao
- Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, Taipa, Macau, China
| | - Miao Liu
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
| | - Meng-Yuan Dai
- Department of Gynecological Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China.
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36
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Yadav R, Khatkar R, Yap KCH, Kang CYH, Lyu J, Singh RK, Mandal S, Mohanta A, Lam HY, Okina E, Kumar RR, Uttam V, Sharma U, Jain M, Prakash H, Tuli HS, Kumar AP, Jain A. The miRNA and PD-1/PD-L1 signaling axis: an arsenal of immunotherapeutic targets against lung cancer. Cell Death Discov 2024; 10:414. [PMID: 39343796 PMCID: PMC11439964 DOI: 10.1038/s41420-024-02182-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 08/21/2024] [Accepted: 09/18/2024] [Indexed: 10/01/2024] Open
Abstract
Lung cancer is a severe challenge to the health care system with intrinsic resistance to first and second-line chemo/radiotherapies. In view of the sterile environment of lung cancer, several immunotherapeutic drugs including nivolumab, pembrolizumab, atezolizumab, and durvalumab are currently being used in clinics globally with the intention of releasing exhausted T-cells back against refractory tumor cells. Immunotherapies have a limited response rate and may cause immune-related adverse events (irAEs) in some patients. Hence, a deeper understanding of regulating immune checkpoint interactions could significantly enhance lung cancer treatments. In this review, we explore the role of miRNAs in modulating immunogenic responses against tumors. We discuss various aspects of how manipulating these checkpoints can bias the immune system's response against lung cancer. Specifically, we examine how altering the miRNA profile can impact the activity of various immune checkpoint inhibitors, focusing on the PD-1/PD-L1 pathway within the complex landscape of lung cancer. We believe that a clear understanding of the host's miRNA profile can influence the efficacy of checkpoint inhibitors and significantly contribute to existing immunotherapies for lung cancer patients. Additionally, we discuss ongoing clinical trials involving immunotherapeutic drugs, both as standalone treatments and in combination with other therapies, intending to advance the development of immunotherapy for lung cancer.
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Affiliation(s)
- Ritu Yadav
- Non-Coding RNA and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Rinku Khatkar
- Non-Coding RNA and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Kenneth C-H Yap
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Chloe Yun-Hui Kang
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Juncheng Lyu
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Rahul Kumar Singh
- Non-Coding RNA and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Surojit Mandal
- Non-Coding RNA and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Adrija Mohanta
- Non-Coding RNA and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Hiu Yan Lam
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Elena Okina
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Rajiv Ranjan Kumar
- Non-Coding RNA and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Vivek Uttam
- Non-Coding RNA and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Uttam Sharma
- Non-Coding RNA and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Manju Jain
- Department of Biochemistry, Central University of Punjab, Bathinda, Punjab, India
| | | | | | - Alan Prem Kumar
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
| | - Aklank Jain
- Non-Coding RNA and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India.
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Lopez CB, Ruijgrok E, van Eijck CHJ. A new era with advanced immunotherapy. Transl Gastroenterol Hepatol 2024; 9:60. [PMID: 39503024 PMCID: PMC11535801 DOI: 10.21037/tgh-24-37] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Accepted: 08/06/2024] [Indexed: 11/08/2024] Open
Affiliation(s)
| | | | - Casper H. J. van Eijck
- Department of Pulmonary Medicine, Erasmus MC, Rotterdam, The Netherlands
- Department of Surgery, Erasmus MC, Rotterdam, The Netherlands
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38
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Li W, Chen G, Peng H, Zhang Q, Nie D, Guo T, Zhu Y, Zhang Y, Lin M. Research Progress on Dendritic Cells in Hepatocellular Carcinoma Immune Microenvironments. Biomolecules 2024; 14:1161. [PMID: 39334927 PMCID: PMC11430656 DOI: 10.3390/biom14091161] [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: 07/17/2024] [Revised: 08/29/2024] [Accepted: 09/05/2024] [Indexed: 09/30/2024] Open
Abstract
Dendritic cells (DCs) are antigen-presenting cells that play a crucial role in initiating immune responses by cross-presenting relevant antigens to initial T cells. The activation of DCs is a crucial step in inducing anti-tumor immunity. Upon recognition and uptake of tumor antigens, activated DCs present these antigens to naive T cells, thereby stimulating T cell-mediated immune responses and enhancing their ability to attack tumors. It is particularly noted that DCs are able to cross-present foreign antigens to major histocompatibility complex class I (MHC-I) molecules, prompting CD8+ T cells to proliferate and differentiate into cytotoxic T cells. In the malignant progression of hepatocellular carcinoma (HCC), the inactivation of DCs plays an important role, and the activation of DCs is particularly important in anti-HCC immunotherapy. In this review, we summarize the mechanisms of DCs activation in HCC, the involved regulatory factors and strategies to activate DCs in HCC immunotherapy. It provides a basis for the study of HCC immunotherapy through DCs activation.
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Affiliation(s)
- Wenya Li
- The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou 225300, China
- Graduate School, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Guojie Chen
- The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou 225300, China
- Medical School, Nantong University, Nantong 226019, China
| | - Hailin Peng
- The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou 225300, China
| | - Qingfang Zhang
- The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou 225300, China
| | - Dengyun Nie
- The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou 225300, China
- Graduate School, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Ting Guo
- The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou 225300, China
- Graduate School, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Yinxing Zhu
- The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou 225300, China
| | - Yuhan Zhang
- The First School of Clinical Medicine Southern Medical University, Guangzhou 510515, China
| | - Mei Lin
- The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou 225300, China
- Graduate School, Nanjing University of Chinese Medicine, Nanjing 210023, China
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39
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Patel AM, Willingham A, Cheng AC, Tomazela D, Bowman E, Kofman E, Zhang F, Bao J, Sanzone JR, Choy JW, Flygare JA, Han JH, Pradhan K, Kieffer M, Chernyak N, Akbari P, Liu P, Mehmood R, Naravula S, Hollingsworth SA, Bhagwat B, Lang SB, Seganish WM. Design and Optimization of Selectivity-Tunable Toll-like Receptor 7/8 Agonists as Novel Antibody-Drug Conjugate Payloads. J Med Chem 2024; 67:15756-15779. [PMID: 39172064 DOI: 10.1021/acs.jmedchem.4c01384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/23/2024]
Abstract
Toll-like receptors 7 and 8 are involved in modulating the adaptive and innate immune responses, and their activation has shown promise as a therapeutic strategy in the field of immuno-oncology. While systemic exposure to TLR7/8 agonists can result in poor tolerance, combination therapies and targeted delivery through antibody-drug conjugates (ADCs) can help mitigate adverse effects. Described herein is the identification of a novel and potent series of pyrazolopyrimidine-based TLR7/8 agonists with tunable receptor selectivity. Representative agonists from this series were successfully able to induce the production of various proinflammatory cytokines and chemokines from human peripheral blood mononuclear cells. Anti-HER2-25 and anti-HER2-26 ADCs made from this class of payloads demonstrated mechanism-based activation of TLR7/8 in a THP1/N87 coculture system.
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Affiliation(s)
- Akash M Patel
- Discovery Chemistry, Merck & Co. Inc., South San Francisco, California 94080, United States
| | - Aarron Willingham
- Discovery Biologics, Merck & Co. Inc., South San Francisco, California 94080, United States
| | - Alan C Cheng
- Modeling and Informatics, Merck & Co. Inc., South San Francisco, California 94080, United States
| | - Daniela Tomazela
- Discovery Biologics, Merck & Co. Inc., South San Francisco, California 94080, United States
| | - Eddie Bowman
- Discovery Oncology, Merck & Co. Inc., South San Francisco, California 94080, United States
| | - Esther Kofman
- Discovery Biologics, Merck & Co. Inc., South San Francisco, California 94080, United States
| | - Fan Zhang
- Discovery Biologics, Merck & Co. Inc., South San Francisco, California 94080, United States
| | - Jianming Bao
- External Discovery Chemistry, Merck & Co. Inc., South San Francisco, California 94080, United States
| | - Jillian R Sanzone
- External Discovery Chemistry, Merck & Co. Inc., South San Francisco, California 94080, United States
| | - Jonathan W Choy
- Discovery Oncology, Merck & Co. Inc., South San Francisco, California 94080, United States
| | - John A Flygare
- Discovery Chemistry, Merck & Co. Inc., South San Francisco, California 94080, United States
| | - Jin-Hwan Han
- Discovery Oncology, Merck & Co. Inc., South San Francisco, California 94080, United States
| | - Komal Pradhan
- Discovery Oncology, Merck & Co. Inc., South San Francisco, California 94080, United States
| | - Madeleine Kieffer
- Discovery Chemistry, Merck & Co. Inc., South San Francisco, California 94080, United States
| | - Natalia Chernyak
- Discovery Chemistry, Merck & Co. Inc., South San Francisco, California 94080, United States
| | - Peyman Akbari
- Discovery Oncology, Merck & Co. Inc., South San Francisco, California 94080, United States
| | - Ping Liu
- External Discovery Chemistry, Merck & Co. Inc., South San Francisco, California 94080, United States
| | - Rimsha Mehmood
- Modeling and Informatics, Merck & Co. Inc., South San Francisco, California 94080, United States
| | - Saraswathi Naravula
- Discovery Biologics, Merck & Co. Inc., South San Francisco, California 94080, United States
| | - Scott A Hollingsworth
- Modeling and Informatics, Merck & Co. Inc., South San Francisco, California 94080, United States
| | - Bhagyashree Bhagwat
- Discovery Biologics, Merck & Co. Inc., South San Francisco, California 94080, United States
| | - Simon B Lang
- Discovery Chemistry, Merck & Co. Inc., South San Francisco, California 94080, United States
| | - W Michael Seganish
- Discovery Chemistry, Merck & Co. Inc., South San Francisco, California 94080, United States
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40
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Hoshi R, Gorospe KA, Labouta HI, Azad T, Lee WL, Thu KL. Alternative Strategies for Delivering Immunotherapeutics Targeting the PD-1/PD-L1 Immune Checkpoint in Cancer. Pharmaceutics 2024; 16:1181. [PMID: 39339217 PMCID: PMC11434872 DOI: 10.3390/pharmaceutics16091181] [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: 08/05/2024] [Revised: 09/01/2024] [Accepted: 09/02/2024] [Indexed: 09/30/2024] Open
Abstract
The programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint constitutes an inhibitory pathway best known for its regulation of cluster of differentiation 8 (CD8)+ T cell-mediated immune responses. Engagement of PD-L1 with PD-1 expressed on CD8+ T cells activates downstream signaling pathways that culminate in T cell exhaustion and/or apoptosis. Physiologically, these immunosuppressive effects exist to prevent autoimmunity, but cancer cells exploit this pathway by overexpressing PD-L1 to facilitate immune escape. Intravenously (IV) administered immune checkpoint inhibitors (ICIs) that block the interaction between PD-1/PD-L1 have achieved great success in reversing T cell exhaustion and promoting tumor regression in various malignancies. However, these ICIs can cause immune-related adverse events (irAEs) due to off-tumor toxicities which limits their therapeutic potential. Therefore, considerable effort has been channeled into exploring alternative delivery strategies that enhance tumor-directed delivery of PD-1/PD-L1 ICIs and reduce irAEs. Here, we briefly describe PD-1/PD-L1-targeted cancer immunotherapy and associated irAEs. We then provide a detailed review of alternative delivery approaches, including locoregional (LDD)-, oncolytic virus (OV)-, nanoparticle (NP)-, and ultrasound and microbubble (USMB)-mediated delivery that are currently under investigation for enhancing tumor-specific delivery to minimize toxic off-tumor effects. We conclude with a commentary on key challenges associated with these delivery methods and potential strategies to mitigate them.
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Affiliation(s)
- Ryunosuke Hoshi
- Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, St. George Campus, Toronto, ON M5S 1A8, Canada; (R.H.); (K.A.G.); (W.L.L.)
- Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Toronto, ON M5B 1T8, Canada;
| | - Kristyna A. Gorospe
- Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, St. George Campus, Toronto, ON M5S 1A8, Canada; (R.H.); (K.A.G.); (W.L.L.)
- Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Toronto, ON M5B 1T8, Canada;
| | - Hagar I. Labouta
- Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Toronto, ON M5B 1T8, Canada;
- Leslie Dan Faculty of Pharmacy, University of Toronto, St. George Campus, Toronto, ON M5S 3M2, Canada
- Biomedical Engineering, Faculty of Applied Science and Engineering, University of Toronto, St. George Campus, Toronto, ON M5S 3E2, Canada
| | - Taha Azad
- Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Health Campus, Sherbrooke, QC J1K 2R1, Canada;
- Research Center, Centre Hospitalier Universitaire de Sherbrooke (CHUS), Sherbrooke, QC J1J 3H5, Canada
| | - Warren L. Lee
- Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, St. George Campus, Toronto, ON M5S 1A8, Canada; (R.H.); (K.A.G.); (W.L.L.)
- Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Toronto, ON M5B 1T8, Canada;
- Biochemistry, Temerty Faculty of Medicine, University of Toronto, St. George Campus, Toronto, ON M5S 1A8, Canada
- Medicine and the Interdepartmental Division of Critical Care Medicine, Temerty Faculty of Medicine, University of Toronto, St. George Campus, Toronto, ON M5B 1T8, Canada
| | - Kelsie L. Thu
- Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, St. George Campus, Toronto, ON M5S 1A8, Canada; (R.H.); (K.A.G.); (W.L.L.)
- Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Toronto, ON M5B 1T8, Canada;
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Kamaraj R, Ghosh S, Das S, Sen S, Kumar P, Majumdar M, Dasgupta R, Mukherjee S, Das S, Ghose I, Pavek P, Raja Karuppiah MP, Chuturgoon AA, Anand K. Targeted Protein Degradation (TPD) for Immunotherapy: Understanding Proteolysis Targeting Chimera-Driven Ubiquitin-Proteasome Interactions. Bioconjug Chem 2024; 35:1089-1115. [PMID: 38990186 PMCID: PMC11342303 DOI: 10.1021/acs.bioconjchem.4c00253] [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: 06/05/2024] [Revised: 07/02/2024] [Accepted: 07/03/2024] [Indexed: 07/12/2024]
Abstract
Targeted protein degradation or TPD, is rapidly emerging as a treatment that utilizes small molecules to degrade proteins that cause diseases. TPD allows for the selective removal of disease-causing proteins, including proteasome-mediated degradation, lysosome-mediated degradation, and autophagy-mediated degradation. This approach has shown great promise in preclinical studies and is now being translated to treat numerous diseases, including neurodegenerative diseases, infectious diseases, and cancer. This review discusses the latest advances in TPD and its potential as a new chemical modality for immunotherapy, with a special focus on the innovative applications and cutting-edge research of PROTACs (Proteolysis TArgeting Chimeras) and their efficient translation from scientific discovery to technological achievements. Our review also addresses the significant obstacles and potential prospects in this domain, while also offering insights into the future of TPD for immunotherapeutic applications.
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Affiliation(s)
- Rajamanikkam Kamaraj
- Department
of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University in Prague, Heyrovskeho 1203, 50005 Hradec Kralove, Czech Republic
| | - Subhrojyoti Ghosh
- Department
of Biotechnology, Indian Institute of Technology
Madras, Chennai 600036, India
| | - Souvadra Das
- Department
of Biotechnology, Heritage Institute of
Technology, Kolkata 700107, India
| | - Shinjini Sen
- Department
of Biotechnology, Heritage Institute of
Technology, Kolkata 700107, India
| | - Priyanka Kumar
- Department
of Biotechnology, Heritage Institute of
Technology, Kolkata 700107, India
| | - Madhurima Majumdar
- Department
of Biotechnology, Heritage Institute of
Technology, Kolkata 700107, India
| | - Renesa Dasgupta
- Department
of Biotechnology, Heritage Institute of
Technology, Kolkata 700107, India
| | - Sampurna Mukherjee
- Department
of Biotechnology, Heritage Institute of
Technology, Kolkata 700107, India
| | - Shrimanti Das
- Department
of Biotechnology, Heritage Institute of
Technology, Kolkata 700107, India
| | - Indrilla Ghose
- Department
of Biotechnology, Heritage Institute of
Technology, Kolkata 700107, India
| | - Petr Pavek
- Department
of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University in Prague, Heyrovskeho 1203, 50005 Hradec Kralove, Czech Republic
| | - Muruga Poopathi Raja Karuppiah
- Department
of Chemistry, School of Physical Sciences, Central University of Kerala, Tejaswini Hills, Periye, Kasaragod District, Kerala 671320, India
| | - Anil A. Chuturgoon
- Discipline
of Medical Biochemistry, School of Laboratory Medicine and Medical
Sciences, College of Health Sciences, Howard College Campus, University of KwaZulu-Natal, Durban 4041, South Africa
| | - Krishnan Anand
- Department
of Chemical Pathology, School of Pathology, Faculty of Health Sciences, University of the Free State, Bloemfontein, Free State 9300, South Africa
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Tong Y, Zhu T, Xu F, Yang W, Wang Y, Zhang X, Chen X, Liu L. Construction of an immune-related gene prognostic model for obese endometrial cancer patients based on bioinformatics analysis. Heliyon 2024; 10:e35488. [PMID: 39170242 PMCID: PMC11336703 DOI: 10.1016/j.heliyon.2024.e35488] [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: 01/03/2024] [Revised: 07/25/2024] [Accepted: 07/30/2024] [Indexed: 08/23/2024] Open
Abstract
Background The tumor microenvironment (TME) affected the prognosis of tumors. However, its effect on the outcomes of obese endometrial cancer (EC) patients had not been reported. Methods This research performed a retrospective analysis of the transcriptome profiles and medical data of 503 EC patients. Immune scores were assessed by estimation algorithms. Cox and LASSO regression analyses were utilized to pinpoint key genes linked to prognosis, and the RPS was created to forecast the outcomes of obese EC patients. The relationship among genetic mutations and RPS was examined using CNV and somatic mutation information. ssGSEA and GSVA were employed to detect immune infiltration and immune pathway enrichment associated with key genes. The TIDE algorithm and GDSC database were utilized to forecast patients' responses of patients to immunotherapy and chemotherapy, respectively. Finally, we employed the 'rms' R software package to construct the nomogram. Results The prognosis of obese EC patients was associated with immune scores. Three key genes (EYA4, MBOAT2 and SCGB2A1) were identified. The risk prognosis score (RPS) for obese EC patients was established by risk stratification and prognostic prediction using prognostic genes. The higher the RPS, the worse the prognosis, and the more malignant the genomic alterations. The high RPS group had a significantly reduced proportion of most immune cells in comparison to the low RPS group. The high RPS group was linked to G2M, MYC and E2F related pathways such as cell proliferation, cell cycle and cell death. Cisplatin, tamoxifen and topotecan had a greater effect on the low RPS group. Notably, the nomogram had a good predictive ability. Conclusion Our study designed a reliable RPS for obese EC patients to forecast their prognosis, immune aggressiveness, and responses to immunotherapy and drug treatments.
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Affiliation(s)
- Yun Tong
- Department of Pharmacogenomics, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China
| | - Tao Zhu
- Department of Pharmacy, Beidahuang Industry Group General Hospital, Harbin, 150088, China
| | - Fei Xu
- Department of Pharmacogenomics, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China
| | - Wenjun Yang
- Department of Pharmacogenomics, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China
| | - Yakun Wang
- Department of Pharmacogenomics, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China
| | - Xianze Zhang
- Department of Pharmacogenomics, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China
| | - Xiujie Chen
- Department of Pharmacogenomics, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China
| | - Lei Liu
- Department of Pharmacogenomics, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China
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Wang H, Gong L, Huang X, White SD, Chung HT, Vesprini D, Petchiny TN, Fokas E, He H, Kerbel RS, Liu SK. Potentiating Salvage Radiotherapy in Radiorecurrent Prostate Cancer Through Anti-CTLA4 Therapy: Implications from a Syngeneic Model. Cancers (Basel) 2024; 16:2839. [PMID: 39199612 PMCID: PMC11352774 DOI: 10.3390/cancers16162839] [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: 07/09/2024] [Revised: 08/02/2024] [Accepted: 08/08/2024] [Indexed: 09/01/2024] Open
Abstract
High-risk prostate cancer (PCa) is a leading cause in cancer death and can elicit significant morbidity and mortality. Currently, the salvage of local disease recurrence after radiation therapy (RT) is a major clinical problem. Immune checkpoint inhibitors (ICIs), which enhance immune activation, have demonstrated clinical therapeutic promise in combination with ionizing radiation (IR) in certain advanced cancers. We generated the TRAMP-C2 HF radiorecurrent syngeneic mouse model to evaluate the therapeutic efficacy of ICIs in combination with RT. The administration of anti-PDL1 and/or anti-CTLA4 did not achieve a significant tumor growth delay compared to the control. The combination of IR and anti-PDL1 did not yield additional a growth delay compared to IR and the isotype control. Strikingly, a significant tumor growth delay and complete cure in one-third of the mice were seen with the combination of IR and anti-CTLA4. Immune cells in tumor-draining lymph nodes and tumor-infiltrating lymphocytes from mice treated with IR and anti-CTLA4 demonstrated an upregulation of genes in T-cell functions and enrichment in both CD4+ and CD8+ T-cell populations compared to mice given IR and the isotype control. Taken together, these results indicate enhancement of T-cell response in radiorecurrent PCa by IR and anti-CTLA4.
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Affiliation(s)
- Hanzhi Wang
- Department of Medical Biophysics, University of Toronto, Toronto, ON M5S 1L7, Canada; (L.G.); (S.D.W.); (H.H.); (R.S.K.); (S.K.L.)
- Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada; (X.H.); (D.V.); (T.N.P.)
| | - Linsey Gong
- Department of Medical Biophysics, University of Toronto, Toronto, ON M5S 1L7, Canada; (L.G.); (S.D.W.); (H.H.); (R.S.K.); (S.K.L.)
| | - Xiaoyong Huang
- Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada; (X.H.); (D.V.); (T.N.P.)
| | - Stephanie D. White
- Department of Medical Biophysics, University of Toronto, Toronto, ON M5S 1L7, Canada; (L.G.); (S.D.W.); (H.H.); (R.S.K.); (S.K.L.)
- Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada; (X.H.); (D.V.); (T.N.P.)
| | - Hans T. Chung
- Sunnybrook Health Sciences Centre, Odette Cancer Centre, Toronto, ON M4N 3M5, Canada;
- Department of Radiation Oncology, University of Toronto, Toronto, ON M5S 1P5, Canada
| | - Danny Vesprini
- Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada; (X.H.); (D.V.); (T.N.P.)
- Sunnybrook Health Sciences Centre, Odette Cancer Centre, Toronto, ON M4N 3M5, Canada;
- Department of Radiation Oncology, University of Toronto, Toronto, ON M5S 1P5, Canada
| | - Tera N. Petchiny
- Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada; (X.H.); (D.V.); (T.N.P.)
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Emmanouil Fokas
- Department of Radiation Oncology, CyberKnife and Radiation Therapy, Centre for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), Faculty of Medicine, University Hospital of Cologne, University of Cologne, 50937 Cologne, Germany;
| | - Hansen He
- Department of Medical Biophysics, University of Toronto, Toronto, ON M5S 1L7, Canada; (L.G.); (S.D.W.); (H.H.); (R.S.K.); (S.K.L.)
- Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 2C4, Canada
| | - Robert S. Kerbel
- Department of Medical Biophysics, University of Toronto, Toronto, ON M5S 1L7, Canada; (L.G.); (S.D.W.); (H.H.); (R.S.K.); (S.K.L.)
- Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada; (X.H.); (D.V.); (T.N.P.)
| | - Stanley K. Liu
- Department of Medical Biophysics, University of Toronto, Toronto, ON M5S 1L7, Canada; (L.G.); (S.D.W.); (H.H.); (R.S.K.); (S.K.L.)
- Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada; (X.H.); (D.V.); (T.N.P.)
- Sunnybrook Health Sciences Centre, Odette Cancer Centre, Toronto, ON M4N 3M5, Canada;
- Department of Radiation Oncology, University of Toronto, Toronto, ON M5S 1P5, Canada
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Shi Y, Li X, Zhang J. Systematic review on the role of the gut microbiota in tumors and their treatment. Front Endocrinol (Lausanne) 2024; 15:1355387. [PMID: 39175566 PMCID: PMC11338852 DOI: 10.3389/fendo.2024.1355387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Accepted: 07/23/2024] [Indexed: 08/24/2024] Open
Abstract
Tumors present a formidable health risk with limited curability and high mortality; existing treatments face challenges in addressing the unique tumor microenvironment (hypoxia, low pH, and high permeability), necessitating the development of new therapeutic approaches. Under certain circumstances, certain bacteria, especially anaerobes or parthenogenetic anaerobes, accumulate and proliferate in the tumor environment. This phenomenon activates a series of responses in the body that ultimately produce anti-tumor effects. These bacteria can target and colonize the tumor microenvironment, promoting responses aimed at targeting and fighting tumor cells. Understanding and exploiting such interactions holds promise for innovative therapeutic strategies, potentially augmenting existing treatments and contributing to the development of more effective and targeted approaches to fighting tumors. This paper reviews the tumor-promoting mechanisms and anti-tumor effects of the digestive tract microbiome and describes bacterial therapeutic strategies for tumors, including natural and engineered anti-tumor strategies.
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Affiliation(s)
- Ying Shi
- School of Pharmacy, University College London, London, United Kingdom
- China Medical University Joint Queen’s University of Belfast, China Medical University, Shenyang, Liaoning, China
| | - Xiao Li
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Jin Zhang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
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Langouo Fontsa M, Padonou F, Willard-Gallo K. Tumor-associated tertiary lymphoid structures in cancer: implications for immunotherapy. Expert Rev Clin Immunol 2024; 20:839-847. [PMID: 39007892 DOI: 10.1080/1744666x.2024.2380892] [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: 03/22/2023] [Accepted: 07/12/2024] [Indexed: 07/16/2024]
Abstract
INTRODUCTION Tertiary lymphoid structures (TLS) arise at chronic inflammatory sites where they function as miniature lymph nodes to generate immune responses, which can be beneficial or detrimental, in diseases as diverse as autoimmunity, chronic infections and cancer. A growing number of studies show that a TLS presence in tumors from cancer patients treated with immune checkpoint inhibitors is closely linked with improved clinical outcomes. TLS may foster the generation of specific anti-tumor immune responses and immunological memory that recognizes a patient's own tumor. Due to repeated rounds of chronic inflammation, some tumor-associated TLS may be immunologically inactive, with immune checkpoint inhibitors functioning to revitalize them through pathway activation. AREAS COVERED This review summarizes work on TLS and how they mediate immune responses in human tumors. We also explore TLS as potential prognostic and predictive biomarkers for immunotherapy. EXPERT OPINION The presence of TLS in human tumors has been linked with a better clinical prognosis, response to treatment(s) and overall survival. TLS provide a structured microenvironment for the activation, expansion and maturation of immune cells at the tumor site. These activities can enhance the efficacy of immunotherapeutic treatments such as checkpoint inhibitors and cancer vaccines by revitalizing local anti-tumor immunity.
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Affiliation(s)
- Mireille Langouo Fontsa
- Molecular Immunology Unit, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
| | - Francine Padonou
- Molecular Immunology Unit, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
| | - Karen Willard-Gallo
- Molecular Immunology Unit, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
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Koh YR, Cummings KC. Newer Immunosuppressants for Rheumatologic Disease: Preoperative Considerations. Rheum Dis Clin North Am 2024; 50:545-557. [PMID: 38942584 DOI: 10.1016/j.rdc.2024.03.006] [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] [Indexed: 06/30/2024]
Abstract
With the advent of small-molecule immune modulators, recombinant fusion proteins, and monoclonal antibodies, treatment options for patients with rheumatic diseases are now broad. These agents carry significant risks and an individualized approach to each patient, balancing known risks and benefits, remains the most prudent course. This review summarizes the available immunosuppressant treatments, discusses their perioperative implications, and provides recommendations for their perioperative management.
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Affiliation(s)
- Ye Rin Koh
- Anesthesiology Institute, Cleveland Clinic, 9500 Euclid Avenue, E-31, Cleveland, OH 44195, USA
| | - Kenneth C Cummings
- Anesthesiology Institute, Cleveland Clinic, 9500 Euclid Avenue, E-31, Cleveland, OH 44195, USA.
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47
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Duda-Madej A, Viscardi S, Szewczyk W, Topola E. Natural Alkaloids in Cancer Therapy: Berberine, Sanguinarine and Chelerythrine against Colorectal and Gastric Cancer. Int J Mol Sci 2024; 25:8375. [PMID: 39125943 PMCID: PMC11313295 DOI: 10.3390/ijms25158375] [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: 07/18/2024] [Revised: 07/27/2024] [Accepted: 07/29/2024] [Indexed: 08/12/2024] Open
Abstract
The rising incidence of colorectal cancer (CRC) and gastric cancer (GC) worldwide, coupled with the limited effectiveness of current chemotherapeutic agents, has prioritized the search for new therapeutic options. Natural substances, which often exhibit cytostatic properties, hold significant promise in this area. This review evaluates the anticancer properties of three natural alkaloids-berberine, sanguinarine, and chelerythrine-against CRC and GC. In vivo and in vitro studies have demonstrated that these substances can reduce tumor volume and inhibit the epithelial-mesenchymal transition (EMT) of tumors. At the molecular level, these alkaloids disrupt key signaling pathways in cancer cells, including mTOR, MAPK, EGFR, PI3K/AKT, and NF-κB. Additionally, they exhibit immunomodulatory effects, leading to the induction of programmed cell death through both apoptosis and autophagy. Notably, these substances have shown synergistic effects when combined with classical cytostatic agents such as cyclophosphamide, 5-fluorouracil, cetuximab, and erlotinib. Furthermore, berberine has demonstrated the ability to restore sensitivity in individuals originally resistant to cisplatin GC. Given these findings, natural compounds emerge as a promising option in the chemotherapy of malignant gastrointestinal tumors, particularly in cases with limited treatment options. However, more research is necessary to fully understand their therapeutic potential.
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Affiliation(s)
- Anna Duda-Madej
- Department of Microbiology, Faculty of Medicine, Wroclaw Medical University, Chałubińskiego 4, 50-368 Wrocław, Poland
| | - Szymon Viscardi
- Faculty of Medicine, Wroclaw Medical University, Ludwika Pasteura 1, 50-367 Wrocław, Poland; (S.V.); (W.S.); (E.T.)
| | - Wiktoria Szewczyk
- Faculty of Medicine, Wroclaw Medical University, Ludwika Pasteura 1, 50-367 Wrocław, Poland; (S.V.); (W.S.); (E.T.)
| | - Ewa Topola
- Faculty of Medicine, Wroclaw Medical University, Ludwika Pasteura 1, 50-367 Wrocław, Poland; (S.V.); (W.S.); (E.T.)
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Abdelazeem KN, Nguyen D, Corbo S, Darragh LB, Matsumoto MW, Court BV, Neupert B, Yu J, Olimpo NA, Osborne DG, Gadwa J, Ross RB, Nguyen A, Bhatia S, Kapoor M, Friedman RS, Jacobelli J, Saviola AJ, Knitz MW, Pasquale EB, Karam SD. Manipulating the EphB4-ephrinB2 axis to reduce metastasis in HNSCC. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.21.604518. [PMID: 39091728 PMCID: PMC11291065 DOI: 10.1101/2024.07.21.604518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/04/2024]
Abstract
The EphB4-ephrinB2 signaling axis has been heavily implicated in metastasis across numerous cancer types. Our emerging understanding of the dichotomous roles that EphB4 and ephrinB2 play in head and neck squamous cell carcinoma (HNSCC) poses a significant challenge to rational drug design. We find that EphB4 knockdown in cancer cells enhances metastasis in preclinical HNSCC models by augmenting immunosuppressive cells like T regulatory cells (Tregs) within the tumor microenvironment. EphB4 inhibition in cancer cells also amplifies their ability to metastasize through increased expression of genes associated with epithelial mesenchymal transition and hallmark pathways of metastasis. In contrast, vascular ephrinB2 knockout coupled with radiation therapy (RT) enhances anti-tumor immunity, reduces Treg accumulation into the tumor, and decreases metastasis. Notably, targeting the EphB4-ephrinB2 signaling axis with the engineered EphB4 ligands EFNB2-Fc-His and Fc-TNYL-RAW-GS reduces local tumor growth and distant metastasis in a preclinical model of HNSCC. Our data suggest that targeted inhibition of vascular ephrinB2 while avoiding inhibition of EphB4 in cancer cells could be a promising strategy to mitigate HNSCC metastasis.
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Affiliation(s)
- Khalid N.M. Abdelazeem
- Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
- Radiation Biology Research Department, National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority, Cairo, Egypt
| | - Diemmy Nguyen
- Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - Sophia Corbo
- Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - Laurel B. Darragh
- Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
- Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Mike W. Matsumoto
- Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Benjamin Van Court
- Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - Brooke Neupert
- Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - Justin Yu
- Department of Otolaryngology - Head and Neck Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Nicholas A. Olimpo
- Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - Douglas Grant Osborne
- Department of Dermatology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Jacob Gadwa
- Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
- Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Richard B. Ross
- Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - Alexander Nguyen
- Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - Shilpa Bhatia
- Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - Mohit Kapoor
- Krembil Research Institute, University Health Network, and University of Toronto, Toronto, Ontario, Canada
| | - Rachel S. Friedman
- Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Barbara Davis Research Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Jordan Jacobelli
- Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Barbara Davis Research Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Anthony J. Saviola
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Center, Aurora, CO, USA
| | - Michael W. Knitz
- Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - Elena B. Pasquale
- Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Sana D. Karam
- Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
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Liu Z, Lei T, Guo Y, Zheng C. The impact of sarcopenia on the efficacy of PD-1 inhibitors in non-small cell lung cancer and potential strategies to overcome resistance. Front Pharmacol 2024; 15:1377666. [PMID: 39101140 PMCID: PMC11294093 DOI: 10.3389/fphar.2024.1377666] [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: 01/28/2024] [Accepted: 06/18/2024] [Indexed: 08/06/2024] Open
Abstract
Recent studies have revealed that sarcopenia can adversely affect the efficacy of PD-1 inhibitors in the treatment of non-small cell lung cancer (NSCLC). PD-1 inhibitors are immune checkpoint inhibitors widely used in the treatment of various cancers. However, NSCLC patients may have poorer outcomes when receiving PD-1 inhibitor treatment, and sarcopenia may affect the efficacy of PD-1 inhibitors through immune and metabolic mechanisms. In this article, we summarize the reported negative impact of sarcopenia on the effectiveness of PD-1 inhibitors in the treatment of NSCLC in recent years. Based on existing research results, we analyze the possible mechanisms by which sarcopenia affects the efficacy of PD-1 inhibitors and discuss possible strategies to address this issue. This could help to understand the impact of sarcopenia on the treatment of PD-1 inhibitors and provide more accurate expectations of treatment outcomes for clinicians and patients. Additionally, we present tailored intervention strategies for sarcopenic patients undergoing PD-1 inhibitor therapy, aiming to optimize treatment efficacy and enhance patient quality of life. Nevertheless, further research is warranted to elucidate the mechanisms through which sarcopenia impacts PD-1 inhibitors and to identify more efficacious intervention approaches for improving the effectiveness of PD-1 inhibitor treatment in sarcopenic patients.
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Affiliation(s)
- Zhenchao Liu
- School of Pharmacy, Qingdao University, Qingdao, Shandong, China
| | - Tianxiang Lei
- Institute of Integrative Medicine, Qingdao University, Qingdao, Shandong, China
| | - Yunliang Guo
- Institute of Integrative Medicine, Qingdao University, Qingdao, Shandong, China
| | - Chongwen Zheng
- Department of Neurology, The 2nd Affiliated Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, China
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Frey C, Etminan M. Adverse Events of PD-1, PD-L1, CTLA-4, and LAG-3 Immune Checkpoint Inhibitors: An Analysis of the FDA Adverse Events Database. Antibodies (Basel) 2024; 13:59. [PMID: 39051335 PMCID: PMC11270294 DOI: 10.3390/antib13030059] [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: 06/28/2024] [Revised: 07/13/2024] [Accepted: 07/16/2024] [Indexed: 07/27/2024] Open
Abstract
This study aimed to identify the 25 most prevalent adverse events (AEs) associated with FDA-approved immune checkpoint inhibitors (ICIs)-specifically, PD-1, PD-L1, CTLA-4, and LAG-3 inhibitors-using data from the FDA Adverse Events Reporting System (FAERS), a publicly available repository of reported drug adverse events, and AERSMine, an open-access pharmacovigilance tool, to investigate these adverse events. For PD-1 inhibitors, the most common AEs were diarrhea, fatigue, and pyrexia, with notable instances of neutropenia and hypothyroidism, particularly with toripalimab and dostarlimab. PD-L1 inhibitors also frequently caused pyrexia, diarrhea, and fatigue, with interstitial lung disease and hypothyroidism showing a class effect, and drug-specific AEs such as hepatotoxicity and chills. CTLA-4 inhibitors predominantly resulted in diarrhea and colitis, with ipilimumab frequently causing pyrexia and rash, while tremelimumab exhibited unique AEs such as biliary tract infection. The LAG-3 inhibitor relatlimab reported fewer AEs, including pyrexia and pneumonia. Rare but significant AEs across all inhibitors included myocarditis and myasthenia gravis. This study provides a detailed overview of the 25 most common AEs associated with ICIs, offering valuable insights for clinical decision-making and AE management. Further research is necessary to elucidate the mechanisms underlying these AEs and to develop targeted interventions to enhance the safety and efficacy of ICI therapy in patients with cancer.
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Affiliation(s)
- Connor Frey
- Department of Medicine, University of British Columbia, 317-2194 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada
| | - Mahyar Etminan
- Department of Ophthalmology and Visual Sciences, University of British Columbia, 2550 Willow Street, Vancouver, BC V5Z 3N9, Canada;
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