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Wang H, Xu F, Wang C. Metabolic reprogramming of tumor microenviroment by engineered bacteria. Semin Cancer Biol 2025; 112:58-70. [PMID: 40157514 DOI: 10.1016/j.semcancer.2025.03.003] [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: 01/31/2025] [Revised: 03/16/2025] [Accepted: 03/21/2025] [Indexed: 04/01/2025]
Abstract
The tumor microenvironment (TME) is a complex ecosystem that plays a crucial role in tumor progression and response to therapy. The metabolic characteristics of the TME are fundamental to its function, influencing not only cancer cell proliferation and survival but also the behavior of immune cells within the tumor. Metabolic reprogramming-where cancer cells adapt their metabolic pathways to support rapid growth and immune evasion-has emerged as a key factor in cancer immunotherapy. Recently, the potential of engineered bacteria in cancer immunotherapy has gained increasing recognition, offering a novel strategy to modulate TME metabolism and enhance antitumor immunity. This review summarizes the metabolic properties and adaptations of tumor and immune cells within the TME and summarizes the strategies by which engineered bacteria regulate tumor metabolism. We discuss how engineered bacteria can overcome the immunosuppressive TME by reprogramming its metabolism to improve antitumor therapy. Furthermore, we examine the advantages, potential challenges, and future clinical translation of engineered bacteria in reshaping TME metabolism.
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Affiliation(s)
- Heng Wang
- Laboratory for Biomaterial and Immunoengineering, Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou, Jiangsu 215123, China
| | - Fang Xu
- Laboratory for Biomaterial and Immunoengineering, Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou, Jiangsu 215123, China
| | - Chao Wang
- Laboratory for Biomaterial and Immunoengineering, Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou, Jiangsu 215123, China.
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2
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Ren S, Pan R, Wang Z. Multi-omics and Single Cell Sequencing Analyses Reveal Associations of Mitophagy-Related Genes Predicting Clinical Prognosis and Immune Infiltration Characteristics in Osteosarcoma. Mol Biotechnol 2024:10.1007/s12033-024-01280-w. [PMID: 39264525 DOI: 10.1007/s12033-024-01280-w] [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] [Accepted: 09/03/2024] [Indexed: 09/13/2024]
Abstract
Despite recent advances in clinical treatments, identifying high-risk osteosarcoma (OS) patients remains an unresolved clinical challenge. Mitophagy, a specialized form of cellular autophagy, selectively reduces the number of mitochondria or repairs their abnormal functions in response to external stress, thereby ensuring mitochondrial quality and maintaining mitochondrial function. Mitophagy plays a crucial role in cancer development, including processes such as mitochondrial repair, homeostasis maintenance, and tumor metabolism. However, its impact on OS has not yet been reported. In this study, we collected 58 mitophagy-related genes (MPRGs) from the TARGET and GEO databases and bioinformatically screened for those associated with OS prognosis. By LASSO-multivariable Cox regression algorithm, we subsequently developed a novel scoring system, the MPRG score, and validated its significance in predicting OS prognosis. Immune landscape analysis showed patients in the low MPRG group had a higher immune infiltration level than those in the high MPRG group. Drug sensitivity differences highlighted the potential need for alternative therapeutic strategies based on MPRG scoring system. The distribution characteristics of the MPRG signature in different cell subtypes of OS were explored by single-cell sequencing analyses. In vitro experiments further confirmed the abnormal expression of screened targets in OS. Our findings highlight the role of mitophagy in OS and its potential as a therapeutic target.
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Affiliation(s)
- Shengquan Ren
- Department of Hand and Foot Microsurgery, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Rongfang Pan
- Department of Nutrition, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Zhengdan Wang
- Department of Hand and Foot Microsurgery, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China.
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Niu B, Tian T, Wang L, Tian Y, Tian T, Guo Y, Zhou H, Zhang Z. CCL9/CCR1 axis-driven chemotactic nanovesicles for attenuating metastasis of SMAD4-deficient colorectal cancer by trapping TGF- β. Acta Pharm Sin B 2024; 14:3711-3729. [PMID: 39220887 PMCID: PMC11365421 DOI: 10.1016/j.apsb.2024.05.009] [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: 01/16/2024] [Revised: 04/09/2024] [Accepted: 04/15/2024] [Indexed: 09/04/2024] Open
Abstract
SMAD4 deficiency in colorectal cancer (CRC) is highly correlated with liver metastasis and high mortality, yet there are few effective precision therapies available. Here, we show that CCR1+-granulocytic myeloid-derived suppressor cells (G-MDSCs) are highly infiltrated in SMAD4-deficient CRC via CCL15/CCR1 and CCL9/CCR1 axis in clinical specimens and mouse models, respectively. The excessive TGF-β, secreted by tumor-infiltrated CCR1+-G-MDSCs, suppresses the immune response of cytotoxic T lymphocytes (CTLs), thus facilitating metastasis. Hereby, we develop engineered nanovesicles displaying CCR1 and TGFBR2 molecules (C/T-NVs) to chemotactically target the tumor driven by CCL9/CCR1 axis and trap TGF-β through TGF-β-TGFBR2 specific binding. Chemotactic C/T-NVs counteract CCR1+-G-MDSC infiltration through competitive responding CCL9/CCR1 axis. C/T-NVs-induced intratumoral TGF-β exhaustion alleviates the TGF-β-suppressed immune response of CTLs. Collectively, C/T-NVs attenuate liver metastasis of SMAD4-deficient CRC. In further exploration, high expression of programmed cell death ligand-1 (PD-L1) is observed in clinical specimens of SMAD4-deficient CRC. Combining C/T-NVs with anti-PD-L1 antibody (aPD-L1) induces tertiary lymphoid structure formation with sustained activation of CTLs, CXCL13+-CD4+ T, CXCR5+-CD20+ B cells, and enhanced secretion of cytotoxic cytokine interleukin-21 and IFN-γ around tumors, thus eradicating metastatic foci. Our strategy elicits pleiotropic antimetastatic immunity, paving the way for nanovesicle-mediated precision immunotherapy in SMAD4-deficient CRC.
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Affiliation(s)
- Boning Niu
- Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Tianyi Tian
- Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Lu Wang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yinmei Tian
- Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Tian Tian
- Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yuanyuan Guo
- Department of Pharmacy, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Hu Zhou
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, High Throughput Drug Screening Platform, Xiamen University, Xiamen 361102, China
| | - Zhiping Zhang
- Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China
- National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Engineering Research Centre for Novel Drug Delivery System, Huazhong University of Science and Technology, Wuhan 430030, China
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Nepal MR, Shah S, Kang KT. Dual roles of myeloid-derived suppressor cells in various diseases: a review. Arch Pharm Res 2024; 47:597-616. [PMID: 39008186 DOI: 10.1007/s12272-024-01504-2] [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: 10/09/2023] [Accepted: 06/30/2024] [Indexed: 07/16/2024]
Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that originate from bone marrow stem cells. In pathological conditions, such as autoimmune disorders, allergies, infections, and cancer, normal myelopoiesis is altered to facilitate the formation of MDSCs. MDSCs were first shown to promote cancer initiation and progression by immunosuppression with the assistance of various chemokines and cytokines. Recently, various studies have demonstrated that MDSCs play two distinct roles depending on the physiological and pathological conditions. MDSCs have protective roles in autoimmune disorders (such as uveoretinitis, multiple sclerosis, rheumatoid arthritis, ankylosing spondylitis, type 1 diabetes, autoimmune hepatitis, inflammatory bowel disease, alopecia areata, and systemic lupus erythematosus), allergies, and organ transplantation. However, they play negative roles in infections and various cancers. Several immunosuppressive functions and mechanisms of MDSCs have been determined in different disease conditions. This review comprehensively discusses the associations between MDSCs and various pathological conditions and briefly describes therapeutic approaches.
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Affiliation(s)
- Mahesh Raj Nepal
- College of Pharmacy, Duksung Women's University, Seoul, South Korea
- Duksung Innovative Drug Center, Duksung Women's University, Seoul, South Korea
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA
| | - Sajita Shah
- College of Pharmacy, Duksung Women's University, Seoul, South Korea
- Duksung Innovative Drug Center, Duksung Women's University, Seoul, South Korea
- The Comprehensive Cancer Center, Department of Radiation Oncology, Ohio State University, Columbus, OH, USA
| | - Kyu-Tae Kang
- College of Pharmacy, Duksung Women's University, Seoul, South Korea.
- Duksung Innovative Drug Center, Duksung Women's University, Seoul, South Korea.
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Sun J, Li X, Wang Q, Chen P, Zhao L, Gao Y. Proteomic profiling and biomarker discovery for predicting the response to PD-1 inhibitor immunotherapy in gastric cancer patients. Front Pharmacol 2024; 15:1349459. [PMID: 38881867 PMCID: PMC11176556 DOI: 10.3389/fphar.2024.1349459] [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: 12/04/2023] [Accepted: 05/08/2024] [Indexed: 06/18/2024] Open
Abstract
Background: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment; however, a significant proportion of gastric cancer (GC) patients do not respond to this therapy. Consequently, there is an urgent need to elucidate the mechanisms underlying resistance to ICIs and identify robust biomarkers capable of predicting the response to ICIs at treatment initiation. Methods: In this study, we collected GC tissues from 28 patients prior to the administration of anti-programmed death 1 (PD-1) immunotherapy and conducted protein quantification using high-resolution mass spectrometry (MS). Subsequently, we analyzed differences in protein expression, pathways, and the tumor microenvironment (TME) between responders and non-responders. Furthermore, we explored the potential of these differences as predictive indicators. Finally, using machine learning algorithms, we screened for biomarkers and constructed a predictive model. Results: Our proteomics-based analysis revealed that low activity in the complement and coagulation cascades pathway (CCCP) and a high abundance of activated CD8 T cells are positive signals corresponding to ICIs. By using machine learning, we successfully identified a set of 10 protein biomarkers, and the constructed model demonstrated excellent performance in predicting the response in an independent validation set (N = 14; area under the curve [AUC] = 0.959). Conclusion: In summary, our proteomic analyses unveiled unique potential biomarkers for predicting the response to PD-1 inhibitor immunotherapy in GC patients, which may provide the impetus for precision immunotherapy.
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Affiliation(s)
- Jiangang Sun
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Xiaojing Li
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Qian Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Peng Chen
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Longfei Zhao
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Yongshun Gao
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
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Wu K, Zhang G, Shen C, Zhu L, Yu C, Sartorius K, Ding W, Jiang Y, Lu Y. Role of T cells in liver metastasis. Cell Death Dis 2024; 15:341. [PMID: 38755133 PMCID: PMC11099083 DOI: 10.1038/s41419-024-06726-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 04/24/2024] [Accepted: 05/07/2024] [Indexed: 05/18/2024]
Abstract
The liver is a major metastatic site (organ) for gastrointestinal cancers (such as colorectal, gastric, and pancreatic cancers) as well as non-gastrointestinal cancers (such as lung, breast, and melanoma cancers). Due to the innate anatomical position of the liver, the apoptosis of T cells in the liver, the unique metabolic regulation of hepatocytes and other potential mechanisms, the liver tends to form an immunosuppressive microenvironment and subsequently form a pre-metastatic niche (PMN), which can promote metastasis and colonization by various tumor cells(TCs). As a result, the critical role of immunoresponse in liver based metastasis has become increasingly appreciated. T cells, a centrally important member of adaptive immune response, play a significant role in liver based metastases and clarifying the different roles of the various T cells subsets is important to guide future clinical treatment. In this review, we first introduce the predisposing factors and related mechanisms of liver metastasis (LM) before introducing the PMN and its transition to LM. Finally, we detail the role of different subsets of T cells in LM and advances in the management of LM in order to identify potential therapeutic targets for patients with LM.
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Affiliation(s)
- Kejia Wu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
- Department of Hepatobiliary and Pancreatic Surgery, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Guozhu Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The Third Affiliated Hospital of Soochow University, Changzhou, China
- Department of Emergency Medicine, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Changbing Shen
- Department of Hepatobiliary and Pancreatic Surgery, Taizhou Second People's Hospital Affiliated with Yangzhou University, Taizhou, China
| | - Li Zhu
- Department of Hepatobiliary and Pancreatic Surgery, The Third Affiliated Hospital of Soochow University, Changzhou, China
- Department of Emergency Medicine, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Chongyuan Yu
- Department of Hepatobiliary and Pancreatic Surgery, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Kurt Sartorius
- School of Laboratory Medicine and Molecular Sciences, University of Kwazulu-Natal, Durban, South Africa
- Africa Hepatopancreatobiliary Cancer Consortium, Mayo Clinic, Jacksonville, FL, USA
| | - Wei Ding
- Department of General Surgery, Wujin Hospital Affiliated with Jiangsu University, Changzhou, China.
- Department of General Surgery, The Wujin Clinical College of Xuzhou Medical University, Changzhou, China.
- Changzhou Medical Center, Nanjing Medical University, Changzhou, China.
| | - Yong Jiang
- Department of Hepatobiliary and Pancreatic Surgery, The Third Affiliated Hospital of Soochow University, Changzhou, China.
| | - Yunjie Lu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China.
- Africa Hepatopancreatobiliary Cancer Consortium, Mayo Clinic, Jacksonville, FL, USA.
- Department of General Surgery, Wujin Hospital Affiliated with Jiangsu University, Changzhou, China.
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Yang EL, Sun ZJ. Nanomedicine Targeting Myeloid-Derived Suppressor Cells Enhances Anti-Tumor Immunity. Adv Healthc Mater 2024; 13:e2303294. [PMID: 38288864 DOI: 10.1002/adhm.202303294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 11/27/2023] [Indexed: 02/13/2024]
Abstract
Cancer immunotherapy, a field within immunology that aims to enhance the host's anti-cancer immune response, frequently encounters challenges associated with suboptimal response rates. The presence of myeloid-derived suppressor cells (MDSCs), crucial constituents of the tumor microenvironment (TME), exacerbates this issue by fostering immunosuppression and impeding T cell differentiation and maturation. Consequently, targeting MDSCs has emerged as crucial for immunotherapy aimed at enhancing anti-tumor responses. The development of nanomedicines specifically designed to target MDSCs aims to improve the effectiveness of immunotherapy by transforming immunosuppressive tumors into ones more responsive to immune intervention. This review provides a detailed overview of MDSCs in the TME and current strategies targeting these cells. Also the benefits of nanoparticle-assisted drug delivery systems, including design flexibility, efficient drug loading, and protection against enzymatic degradation, are highlighted. It summarizes advances in nanomedicine targeting MDSCs, covering enhanced treatment efficacy, safety, and modulation of the TME, laying the groundwork for more potent cancer immunotherapy.
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Affiliation(s)
- En-Li Yang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, Hubei, 430079, China
| | - Zhi-Jun Sun
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, Hubei, 430079, China
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8
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Yuan R, Li J. Role of macrophages and their exosomes in orthopedic diseases. PeerJ 2024; 12:e17146. [PMID: 38560468 PMCID: PMC10979751 DOI: 10.7717/peerj.17146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 03/01/2024] [Indexed: 04/04/2024] Open
Abstract
Exosomes are vesicles with a lipid bilayer structure that carry various active substances, such as proteins, DNA, non-coding RNA, and nucleic acids; these participate in the immune response, tissue formation, and cell communication. Owing to their low immunogenicity, exosomes play a key role in regulating the skeletal immune environment. Macrophages are important immune cells that swallow various cellular and tissue fragments. M1-like and M2-like macrophages differentiate to play pro-inflammatory, anti-inflammatory, and repair roles following stimulation. In recent years, the increase in the population base and the aging of the population have led to a gradual rise in orthopedic diseases, placing a heavy burden on the social medical system and making it urgent to find effective solutions. Macrophages and their exosomes have been demonstrated to be closely associated with the pathogenesis and prognosis of orthopedic diseases. An in-depth understanding of their mechanisms of action and the interaction between them will be helpful for the future clinical treatment of orthopedic diseases. This review focuses on the mechanisms of action, diagnosis, and treatment of orthopedic diseases involving macrophages and their exosomes, including fracture healing, diabetic bone damage, osteosarcoma, and rheumatoid arthritis. In addition, we discuss the prospects and major challenges faced by macrophages and their exosomes in clinical practice.
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Affiliation(s)
- Riming Yuan
- Shengjing Hospital, China Medical University, Shenyang, China
| | - Jianjun Li
- Shengjing Hospital, China Medical University, Shenyang, China
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Yahya MS, Abdel Hamid FF, Radwan NH, Abdelgawad IA, Soliman AF. Clinical assessment of TGFB1 and HP Relative Gene Expression in the Peripheral Blood of Prostate Cancer Patients. Asian Pac J Cancer Prev 2024; 25:709-717. [PMID: 38415559 PMCID: PMC11077105 DOI: 10.31557/apjcp.2024.25.2.709] [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: 11/13/2023] [Accepted: 02/19/2024] [Indexed: 02/29/2024] Open
Abstract
OBJECTIVE This study aimed to assess the relative gene expression level of transforming growth factor-β1 (TGFB1) and haptoglobin (HP) in the peripheral blood of prostate cancer (PCa) patients and evaluate their diagnostic ability. METHODS A total of 125 participants were enrolled in the present study. Among them, 75 PCa patients, 25 benign prostatic hyperplasia (BPH) patients, and 25 healthy volunteers served as the control group. The relative TGFB1 and HP gene expression level was quantified using real-time polymerase chain reaction. Further, free and total PSA levels were determined using electrochemiluminescence assays. RESULTS TGFB1 was significantly over-expressed, whereas HP was significantly downregulated in the peripheral blood of PCa patients compared to BPH and control groups (p-value ranges from 0.034 to <0.001). Moreover, the high expression level of TGFB1 was associated with an increased risk of PCa development with OR=1.412 (95%CI: 1.081-1.869, p= 0.012). TGFB1 and HP relative expression levels had lower diagnostic performance to differentiate PCa from normal and BPH individuals compared to PSA, however, the combination of the tested parameters improved the diagnostic efficacy. CONCLUSIONS TGFB1 and HP relative expression have moderate diagnostic efficacy in discriminating patients with PCa from BPH and healthy subjects. Furthermore, over-expression of TGFB1 may contribute to the pathogenesis of PCa.
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Affiliation(s)
- Mohammed S Yahya
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt.
| | - Fatma F Abdel Hamid
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt.
| | - Noha H Radwan
- Department of Clinical and Chemical Pathology, National Cancer Institute, Cairo University, Cairo, Egypt.
| | - Iman A Abdelgawad
- Department of Clinical and Chemical Pathology, National Cancer Institute, Cairo University, Cairo, Egypt.
| | - Ahmed F Soliman
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt.
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Moraes Ribeiro E, Secker KA, Nitulescu AM, Schairer R, Keppeler H, Wesle A, Schmid H, Schmitt A, Neuber B, Chmiest D, Podavini S, Märklin M, Klimovich B, Schmitt M, Korkmaz F, Lengerke C, Schneidawind C, Schneidawind D. PD-1 checkpoint inhibition enhances the antilymphoma activity of CD19-CAR-iNKT cells that retain their ability to prevent alloreactivity. J Immunother Cancer 2024; 12:e007829. [PMID: 38296597 PMCID: PMC10831439 DOI: 10.1136/jitc-2023-007829] [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] [Accepted: 12/21/2023] [Indexed: 02/03/2024] Open
Abstract
BACKGROUND Relapse and graft-versus-host disease (GVHD) are the main causes of death after allogeneic hematopoietic cell transplantation (HCT). Preclinical murine models and clinical data suggest that invariant natural killer T (iNKT) cells prevent acute and chronic GVHD. In addition, iNKT cells are crucial for efficient immune responses against malignancies and contribute to reduced relapse rates after transplantation. Chimeric antigen receptors (CAR) redirect effector cells to cell surface antigens and enhance killing of target cells. With this study, we aimed to combine enhanced cytotoxicity of CD19-CAR-iNKT cells against lymphoma cells with their tolerogenic properties. METHODS iNKT cells were isolated from peripheral blood mononuclear cells and transduced with an anti-CD19-CAR retrovirus. After in vitro expansion, the functionality of CD19-CAR-iNKT cells was assessed by flow cytometry, image stream analysis and multiplex analysis in single-stimulation or repeated-stimulation assays. Moreover, the immunoregulatory properties of CD19-CAR-iNKT cells were analyzed in apoptosis assays and in mixed lymphocyte reactions. The effect of checkpoint inhibition through nivolumab was analyzed in these settings. RESULTS In this study, we could show that the cytotoxicity of CD19-CAR-iNKT cells was mediated either through engagement of their CAR or their invariant T-cell receptor, which may circumvent loss of response through antigen escape. However, encounter of CD19-CAR-iNKT cells with their target induced a phenotype of exhaustion. Consequently, checkpoint inhibition increased cytokine release, cytotoxicity and survival of CD19-CAR-iNKT cells. Additionally, they showed robust suppression of alloreactive immune responses. CONCLUSION In this work, we demonstrate that CAR-iNKT cells are a powerful cytotherapeutic option to prevent or treat relapse while potentially reducing the risk of GVHD after allogeneic HCT.
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Affiliation(s)
- Emmanuelle Moraes Ribeiro
- Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, Tübingen, Germany
| | - Kathy-Ann Secker
- Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, Tübingen, Germany
| | - Ana-Maria Nitulescu
- Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, Tübingen, Germany
| | - Rebekka Schairer
- Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, Tübingen, Germany
| | - Hildegard Keppeler
- Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, Tübingen, Germany
| | - Anton Wesle
- Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, Tübingen, Germany
| | - Hannes Schmid
- Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, Tübingen, Germany
| | - Anita Schmitt
- Department of Oncology, Hematology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany
| | - Brigitte Neuber
- Department of Oncology, Hematology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany
| | - Daniela Chmiest
- Department of Immunobiology, University of Lausanne, Lausanne, Switzerland
| | - Silvia Podavini
- Department of Immunobiology, University of Lausanne, Lausanne, Switzerland
| | - Melanie Märklin
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany
- Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany
| | - Boris Klimovich
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany
| | - Michael Schmitt
- Department of Oncology, Hematology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany
| | - Fulya Korkmaz
- Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, Tübingen, Germany
| | - Claudia Lengerke
- Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, Tübingen, Germany
| | - Corina Schneidawind
- Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, Tübingen, Germany
- Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland
| | - Dominik Schneidawind
- Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, Tübingen, Germany
- Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland
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11
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Bronte G, Calabrò L, Olivieri F, Procopio AD, Crinò L. The prognostic effects of circulating myeloid-derived suppressor cells in non-small cell lung cancer: systematic review and meta-analysis. Clin Exp Med 2023; 23:1551-1561. [PMID: 36401744 PMCID: PMC10460713 DOI: 10.1007/s10238-022-00946-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 11/07/2022] [Indexed: 11/21/2022]
Abstract
Immunotherapy is the main standard treatment for non-small cell lung cancer (NSCLC) patients. Immune suppressive cells in tumor microenvironment can counteract its efficacy. Myeloid-derived suppressor cells (MDSCs) include two major subsets: polymorphonuclear (PMN-MDSCs) and monocytic (M-MDSCs). Many studies explored the prognostic impact of these cell populations in NSCLC patients. The aim of this systematic review is to select studies for a meta-analysis, which compares prognosis between patients with high vs low circulating MDSC levels. We collected hazard ratios (HRs) and relative 95% confidence intervals (CIs) in terms of progression-free survival (PFS) or recurrence-free survival (RFS), and overall survival (OS). Among 139 studies retrieved from literature search, 14 eligible studies (905 NSCLC patients) met inclusion criteria. Low circulating MDSC levels favor a better PFS/RFS (HR = 1.84; 95% CI = 1.28-2.65) and OS (HR = 1.78; 95% CI = 1.29-2.46). The subgroup analysis based on MDSC subtypes (total-, PMN-, and M-MDSCs) obtained a statistical significance only for M-MDSCs, both in terms of PFS/RFS (HR = 2.67; 95% CI = 2.04-3.50) and OS (HR = 2.10; 95% CI = 1.61-2.75). NSCLC patients bearing high M-MDSC levels in peripheral blood experience a worse prognosis than those with low levels, both in terms of PFS/RFS and OS. This finding suggests that detecting and targeting this MDSC subset could help to improve NSCLC treatment efficacy.
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Affiliation(s)
- Giuseppe Bronte
- Department of Clinical and Molecular Sciences (DISCLIMO), Università Politecnica Delle Marche, Via Tronto 10/A, Ancona, Italy.
- Clinic of Laboratory and Precision Medicine, National Institute of Health and Sciences On Ageing (IRCCS INRCA), Ancona, Italy.
| | - Luana Calabrò
- Medical Oncology Unit, University Hospital of Ferrara, Ferrara, Italy
| | - Fabiola Olivieri
- Department of Clinical and Molecular Sciences (DISCLIMO), Università Politecnica Delle Marche, Via Tronto 10/A, Ancona, Italy
- Clinic of Laboratory and Precision Medicine, National Institute of Health and Sciences On Ageing (IRCCS INRCA), Ancona, Italy
| | - Antonio Domenico Procopio
- Department of Clinical and Molecular Sciences (DISCLIMO), Università Politecnica Delle Marche, Via Tronto 10/A, Ancona, Italy
- Clinic of Laboratory and Precision Medicine, National Institute of Health and Sciences On Ageing (IRCCS INRCA), Ancona, Italy
| | - Lucio Crinò
- Department of Medical Oncology, IRCCS Istituto Romagnolo Per Lo Studio Dei Tumori (IRST) "Dino Amadori", Meldola, Italy
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12
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Wang S, Zhao X, Wu S, Cui D, Xu Z. Myeloid-derived suppressor cells: key immunosuppressive regulators and therapeutic targets in hematological malignancies. Biomark Res 2023; 11:34. [PMID: 36978204 PMCID: PMC10049909 DOI: 10.1186/s40364-023-00475-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 03/15/2023] [Indexed: 03/30/2023] Open
Abstract
The immunosuppressive tumor microenvironment (TME) supports the development of tumors and limits tumor immunotherapy, including hematological malignancies. Hematological malignancies remain a major public health issue with high morbidity and mortality worldwide. As an important component of immunosuppressive regulators, the phenotypic characteristics and prognostic value of myeloid-derived suppressor cells (MDSCs) have received much attention. A variety of MDSC-targeting therapeutic approaches have produced encouraging outcomes. However, the use of various MDSC-targeted treatment strategies in hematologic malignancies is still difficult due to the heterogeneity of hematologic malignancies and the complexity of the immune system. In this review, we summarize the biological functions of MDSCs and further provide a summary of the phenotypes and suppressive mechanisms of MDSC populations expanded in various types of hematological malignancy contexts. Moreover, we discussed the clinical correlation between MDSCs and the diagnosis of malignant hematological disease, as well as the drugs targeting MDSCs, and focused on summarizing the therapeutic strategies in combination with other immunotherapies, such as various immune checkpoint inhibitors (ICIs), that are under active investigation. We highlight the new direction of targeting MDSCs to improve the therapeutic efficacy of tumors.
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Affiliation(s)
- Shifen Wang
- Department of Blood Transfusion, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xingyun Zhao
- Department of Blood Transfusion, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Siwen Wu
- Department of Blood Transfusion, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Dawei Cui
- Department of Blood Transfusion, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Zhenshu Xu
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital, Fuzhou, China.
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13
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Chilakamarthi U, Mahadik NS, Koteshwar D, Krishna NV, Giribabu L, Banerjee R. Potentiation of novel porphyrin based photodynamic therapy against colon cancer with low dose doxorubicin and elucidating the molecular signalling pathways responsible for relapse. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY. B, BIOLOGY 2023; 238:112625. [PMID: 36529058 DOI: 10.1016/j.jphotobiol.2022.112625] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 11/06/2022] [Accepted: 12/06/2022] [Indexed: 12/14/2022]
Abstract
Photodynamic therapy (PDT) is a promising non-invasive treatment modality for cancer and can be potentiated by combination with chemotherapy. Here, we combined PDT of novel porphyrin-based photosensitizers with low dose doxorubicin (Dox) to get maximum outcome. Dox potentiated and showed synergism with PDT under in vitro conditions on CT26.WT cells. The current colon cancer treatment strategies assure partial or even complete tumour regression but loco-regional relapse or distant metastasis is the major cause of death despite combination therapy. The spared cells after the treatment contribute to relapse and it is important to study their behaviour in host environment. Hence, we developed relapse models for PDT, Dox and combination treatments by transplanting respectively treated equal number of live cells to mice (n = 5) for tumour formation. Most of the treated cells lost tumour forming ability, but some treatment resistant cells developed tumours in few mice. These tumours served as relapse models and Western blot analysis of tumour samples provided clinically relevant information to delineate resistance strategies of individual as well as combination therapies at molecular level. Our results showed that low dose Dox helped in increasing the tumour inhibiting effect of PDT in combination therapy, but still there are indeed possibilities of relapse at later stages due to chemoresistance and immune suppression that may occur post-treatment. We observed that the combination therapy may also lead to the development of multidrug resistant (MDR) phenotype during relapse. Thus, this study provided clinically relevant information to further strengthen and improve PDT-drug combination therapy in order to avoid relapse and to treat cancer more effectively.
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Affiliation(s)
- Ushasri Chilakamarthi
- Applied Biology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India.
| | - Namita S Mahadik
- Applied Biology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Devulapally Koteshwar
- Polymers and Functional Materials Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
| | - Narra Vamsi Krishna
- Polymers and Functional Materials Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
| | - Lingamallu Giribabu
- Polymers and Functional Materials Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India.
| | - Rajkumar Banerjee
- Applied Biology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India.
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14
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Takaku S, Shimizu M, Morita R. CD8 + T Cell-Mediated Therapeutic Antitumor Effect of an Herbal Mixture Containing Ganoderma lucidum. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2023; 2023:9630816. [PMID: 37152373 PMCID: PMC10162866 DOI: 10.1155/2023/9630816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 01/09/2023] [Accepted: 03/23/2023] [Indexed: 05/09/2023]
Abstract
Although Kampo-a traditional Japanese herbal medicine-contributes in the control of tumor growth in vivo in experimental animals, most of the antitumor effects are prophylactic and not therapeutic. In this study, we determined whether oral administration of an herbal mixture containing Ganoderma lucidum (WTMCGEP; Wisteria floribunda, Trapae fructus, Myristica fragrans, Coicis semen, Ganoderma lucidum, Elfvingia applanata, and Punica granatum), anecdotally used in Japan for the palliative care of patients with cancer, exhibits a therapeutic effect on tumor growth in vivo in a hypodermic murine CT26 colorectal tumor model. An in vitro tumor assay revealed that WTMCGEP extract has some direct influence over suppression of tumor growth. In wild-type BALB/c mice, WTMCGEP did not show any antitumor effect in vivo. However, in BALB-CD1d-/- mice with partly mitigated immunosuppression by reason of them being devoid of both antitumoral type I and immunosuppressive type II natural killer T (NKT) cells, WTMCGEP therapeutically suppressed tumor growth. CD8+ T cell depletion significantly accelerated tumor growth in WTMCGEP mice; therefore, its antitumor activity was primarily in a CD8+ T cell-dependent manner. Regarding immunosuppressive cells in tumor-bearing CD1d-/- mice, WTMCGEP did not influence the abundance of tumor-infiltrating CD4+ and Forkhead box protein 3+ regulatory T cells. However, it reduced both intratumoral and splenic Ly6G+ Ly6Clo polymorphonuclear myeloid-derived suppressor cells, which were most likely involved in tumor growth inhibition related to higher frequency of intratumoral CD107a+ CD8+ T cells in these mice. Overall, these data illustrate that the deficiency of NKT cells urges WTMCGEP to exert a therapeutic antitumor effect mainly through CD8+ T cells. Our efforts are the first to scientifically demonstrate the WTMCGEP's contribution to tumor immunity.
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Affiliation(s)
- Shun Takaku
- Department of Microbiology and Immunology, Nippon Medical School, Tokyo 113-8602, Japan
- Center for Medical Education, Nippon Medical School, Tokyo 113-8602, Japan
| | - Masumi Shimizu
- Department of Microbiology and Immunology, Nippon Medical School, Tokyo 113-8602, Japan
| | - Rimpei Morita
- Department of Microbiology and Immunology, Nippon Medical School, Tokyo 113-8602, Japan
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15
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Role of NKT cells in cancer immunotherapy-from bench to bed. MEDICAL ONCOLOGY (NORTHWOOD, LONDON, ENGLAND) 2022; 40:29. [PMID: 36460881 DOI: 10.1007/s12032-022-01888-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 11/08/2022] [Indexed: 12/04/2022]
Abstract
Natural killer T (NKT) cells are a specific T cell subset known to express the αβ-T cell receptor (TCR) for antigens identification and express typical NK cell specifications, such as surface expression of CD56 and CD16 markers as well as production of granzyme. Human NKT cells are divided into two subgroups based on their cytokine receptor and TCR repertoire. Both of them are CD1-restricted and recognize lipid antigens presented by CD1d molecules. Studies have demonstrated that these cells are essential in defense against malignancies. These cells secret proinflammatory and regulatory cytokines that stimulate or suppress immune system responses. In several murine tumor models, activation of type I NKT cells induces tumor rejection and inhibits metastasis's spread. However, type II NKT cells are associated with an inhibitory and regulatory function during tumor immune responses. Variant NKT cells may suppress tumor immunity via different mechanisms that require cross-talk with other immune-regulatory cells. NKT-like cells display high tumor-killing abilities against many tumor cells. In the recent decade, different studies have been performed based on the application of NKT-based immunotherapy for cancer therapy. Moreover, manipulation of NKT cells through administering autologous dendritic cell (DC) loaded with α-galactosylceramide (α-GalCer) and direct α-GalCer injection has also been tested. In this review, we described different subtypes of NKT cells, their function in the anti-tumor immune responses, and the application of NKT cells in cancer immunotherapy from bench to bed.
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16
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Wu Y, Yi M, Niu M, Mei Q, Wu K. Myeloid-derived suppressor cells: an emerging target for anticancer immunotherapy. Mol Cancer 2022; 21:184. [PMID: 36163047 PMCID: PMC9513992 DOI: 10.1186/s12943-022-01657-y] [Citation(s) in RCA: 202] [Impact Index Per Article: 67.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 09/19/2022] [Indexed: 02/07/2023] Open
Abstract
The clinical responses observed following treatment with immune checkpoint inhibitors (ICIs) support immunotherapy as a potential anticancer treatment. However, a large proportion of patients cannot benefit from it due to resistance or relapse, which is most likely attributable to the multiple immunosuppressive cells in the tumor microenvironment (TME). Myeloid-derived suppressor cells (MDSCs), a heterogeneous array of pathologically activated immature cells, are a chief component of immunosuppressive networks. These cells potently suppress T-cell activity and thus contribute to the immune escape of malignant tumors. New findings indicate that targeting MDSCs might be an alternative and promising target for immunotherapy, reshaping the immunosuppressive microenvironment and enhancing the efficacy of cancer immunotherapy. In this review, we focus primarily on the classification and inhibitory function of MDSCs and the crosstalk between MDSCs and other myeloid cells. We also briefly summarize the latest approaches to therapies targeting MDSCs.
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Affiliation(s)
- Yuze Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, People's Republic of China
| | - Ming Yi
- Department of Breast Surgery, Zhejiang University School of Medicine First Affiliated Hospital, Hangzhou, 310003, China
| | - Mengke Niu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, People's Republic of China
| | - Qi Mei
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, People's Republic of China. .,Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, Shanxi, People's Republic of China.
| | - Kongming Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, People's Republic of China.
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17
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Abstract
The clinical responses observed following treatment with immune checkpoint inhibitors (ICIs) support immunotherapy as a potential anticancer treatment. However, a large proportion of patients cannot benefit from it due to resistance or relapse, which is most likely attributable to the multiple immunosuppressive cells in the tumor microenvironment (TME). Myeloid-derived suppressor cells (MDSCs), a heterogeneous array of pathologically activated immature cells, are a chief component of immunosuppressive networks. These cells potently suppress T-cell activity and thus contribute to the immune escape of malignant tumors. New findings indicate that targeting MDSCs might be an alternative and promising target for immunotherapy, reshaping the immunosuppressive microenvironment and enhancing the efficacy of cancer immunotherapy. In this review, we focus primarily on the classification and inhibitory function of MDSCs and the crosstalk between MDSCs and other myeloid cells. We also briefly summarize the latest approaches to therapies targeting MDSCs.
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Affiliation(s)
- Yuze Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, People's Republic of China
| | - Ming Yi
- Department of Breast Surgery, Zhejiang University School of Medicine First Affiliated Hospital, Hangzhou, 310003, China
| | - Mengke Niu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, People's Republic of China
| | - Qi Mei
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, People's Republic of China.
- Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, Shanxi, People's Republic of China.
| | - Kongming Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, People's Republic of China.
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18
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Targeting tumour-reprogrammed myeloid cells: the new battleground in cancer immunotherapy. Semin Immunopathol 2022; 45:163-186. [PMID: 36161514 PMCID: PMC9513014 DOI: 10.1007/s00281-022-00965-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 09/13/2022] [Indexed: 11/08/2022]
Abstract
Tumour microenvironment is a complex ecosystem in which myeloid cells are the most abundant immune elements. This cell compartment is composed by different cell types, including neutrophils, macrophages, dendritic cells, and monocytes but also unexpected cell populations with immunosuppressive and pro-tumour roles. Indeed, the release of tumour-derived factors influences physiological haematopoiesis producing unconventional cells with immunosuppressive and tolerogenic functions such as myeloid-derived suppressor cells. These pro-tumour myeloid cell populations not only support immune escape directly but also assist tumour invasion trough non-immunological activities. It is therefore not surprising that these cell subsets considerably impact in tumour progression and cancer therapy resistance, including immunotherapy, and are being investigated as potential targets for developing a new era of cancer therapy. In this review, we discuss emerging strategies able to modulate the functional activity of these tumour-supporting myeloid cells subverting their accumulation, recruitment, survival, and functions. These innovative approaches will help develop innovative, or improve existing, cancer treatments.
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19
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Japanese Kampo Medicine Juzentaihoto Improves Antiviral Cellular Immunity in Tumour-Bearing Hosts. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:6122955. [PMID: 35996405 PMCID: PMC9392631 DOI: 10.1155/2022/6122955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 06/05/2022] [Accepted: 06/07/2022] [Indexed: 12/05/2022]
Abstract
Global and antigen-independent immunosuppression by growing tumours can cause life-threating damage when concurrent with an infection in tumour-bearing hosts. In the present study, we investigated whether the oral administration of the Japanese traditional herbal (Kampo) medicine, juzentaihoto (JTT), plays a role in the improvement of antiviral cellular immunity in tumour-bearing hosts. Female BALB/c mice subcutaneously injected with murine colorectal cancer CT26 cells fed a control or JTT diet were inoculated with recombinant vaccinia virus expressing human immunodeficiency virus-1 glycoprotein 160 (vSC25). At 7 days postinfection, anti-vSC25 cellular immunity was evaluated by measuring the abundance of splenic virus-specific CD8+ T cells. JTT had no impact on CT26 tumour growth in vivo. Surprisingly, JTT augmented anti-vSC25 cellular immunity in CT26-bearing mice. Depletion of either CD25+ regulatory T (Treg) cells or myeloid-derived suppressor cells (MDSCs) also enhanced anti-vSC25 cellular immunity in tumour-bearing mice but had no therapeutic benefit against tumour growth. However, JTT had no impact on the abundance of these immunosuppressive cells. Overall, our data indicates that JTT contributes to the improvement of anti-vSC25 cellular immunity in tumour-bearing hosts possibly via a mechanism independent of CD25+ Treg cells and MDSCs, suggesting that this Kampo medicine can act as a promising antiviral adjuvant in an immunosuppressive state caused by tumours.
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20
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Pramanik A, Bhattacharyya S. Myeloid derived suppressor cells and innate immune system interaction in tumor microenvironment. Life Sci 2022; 305:120755. [PMID: 35780842 DOI: 10.1016/j.lfs.2022.120755] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 06/23/2022] [Accepted: 06/27/2022] [Indexed: 12/24/2022]
Abstract
The tumor microenvironment is a complex domain that not only contains tumor cells but also a plethora of other host immune cells. By nature, the tumor microenvironment is a highly immunosuppressive milieu providing growing conditions for tumor cells. A major immune cell population that contributes most in the development of this immunosuppressive microenvironment is the MDSC, a heterogenous population of immature cells. Although found in small numbers only in the bone marrow of healthy individuals, they readily migrate to the lymph nodes and tumor site during cancer pathogenesis. MDSC mediated disruption of antitumor T cell activity is a major cause of the immunosuppression at the tumor site, but recent findings have shown that MDSC mediated dysfunction of other major immune cells might also play an important role. In this article we will review how crosstalk with MDSC alters the activity of both conventional and unconventional immune cells that inhibits the antitumor immunity and promotes cancer progression.
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Affiliation(s)
- Anik Pramanik
- Immunobiology and Translational Medicine Laboratory, Department of Zoology, Sidho Kanho Birsha University, Purulia 723104, West Bengal, India
| | - Sankar Bhattacharyya
- Immunobiology and Translational Medicine Laboratory, Department of Zoology, Sidho Kanho Birsha University, Purulia 723104, West Bengal, India.
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21
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Sehgal R, Maiwall R, Rajan V, Islam M, Baweja S, Kaur N, Kumar G, Ramakrishna G, Sarin SK, Trehanpati N. Granulocyte-Macrophage Colony-Stimulating Factor Modulates Myeloid-Derived Suppressor Cells and Treg Activity in Decompensated Cirrhotic Patients With Sepsis. Front Immunol 2022; 13:828949. [PMID: 35720398 PMCID: PMC9205181 DOI: 10.3389/fimmu.2022.828949] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 05/03/2022] [Indexed: 11/28/2022] Open
Abstract
Background Decompensated cirrhosis patients are more prone to bacterial infections. Myeloid-derived suppressor cells (MDSCs) expand in sepsis patients and disrupt immune cell functions. Granulocyte-macrophage colony-stimulating factor (GM-CSF) therapy helps in restoring immune cell functions and resolving infections. Its role in MDSC modulation in cirrhosis with sepsis is not well understood. Methods A total of 164 decompensated cirrhotic—62 without (w/o), 72 with sepsis, and 30 with sepsis treated with GM-CSF—and 15 healthy were studied. High-dimensional flow cytometry was performed to analyze MDSCs, monocytes, neutrophils, CD4 T cells, and Tregs at admission and on days 3 and day 7. Ex vivo co-cultured MDSCs with T cells were assessed for proliferation and apoptosis of T cells and differentiation to Tregs. Plasma factors and mRNA levels were analyzed by cytokine-bead assay and qRT-PCR. Results Frequencies of MDSCs and Tregs were significantly increased (p = 0.011 and p = 0.02) with decreased CD4 T cells (p = 0.01) in sepsis than w/o sepsis and healthy controls (HCs) (p = 0.000, p = 0.07, and p = 0.01) at day 0 and day 7. In sepsis patients, MDSCs had increased IL-10, Arg1, and iNOS mRNA levels (p = 0.016, p = 0.043, and p = 0.045). Ex vivo co-cultured MDSCs with T cells drove T-cell apoptosis (p = 0.03, p = 0.03) with decreased T-cell proliferation and enhanced FOXP3+ expression (p = 0.044 and p = 0.043) in sepsis compared to w/o sepsis at day 0. Moreover, blocking the MDSCs with inhibitors suppressed FOXP3 expression. GM-CSF treatment in sepsis patients significantly decreased MDSCs and FOXP3+ Tregs but increased CD4 T-cell functionality and improved survival. Conclusion MDSCs have an immunosuppressive function by expanding FOXP3+ Tregs and inhibiting CD4+ T-cell proliferation in sepsis. GM-CSF treatment suppressed MDSCs, improved T-cell functionality, and reduced Tregs in circulation.
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Affiliation(s)
- Rashi Sehgal
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
- Amity Institute of Biotechnology, Amity University, Noida, India
| | - Rakhi Maiwall
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Vijayaraghavan Rajan
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Mojahidul Islam
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Sukriti Baweja
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Navkiran Kaur
- Amity Institute of Biotechnology, Amity University, Noida, India
| | - Guresh Kumar
- Department of Clinical Research and Biostatistics, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Gayatri Ramakrishna
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Shiv K. Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
- *Correspondence: Nirupma Trehanpati, ; ; Shiv K. Sarin, ;
| | - Nirupma Trehanpati
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
- *Correspondence: Nirupma Trehanpati, ; ; Shiv K. Sarin, ;
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22
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Lawrence M, Wiesheu R, Coffelt SB. The duplexity of unconventional T cells in cancer. Int J Biochem Cell Biol 2022; 146:106213. [PMID: 35447350 DOI: 10.1016/j.biocel.2022.106213] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 04/11/2022] [Accepted: 04/14/2022] [Indexed: 11/29/2022]
Abstract
Unconventional T cells and their involvement in cancer are understudied in comparison to conventional T cells, but recent findings indicate that these cells play important roles in both cancer progression and inhibition. Here, we briefly review the dichotomous role of three unconventional T cell lineages: γδ T cells, MAIT cells and NKT cells. Studies using mouse models of cancer show how this unconventional trilogy interacts with cancer epithelial cells and other immune cell populations during tumour evolution. These reports highlight various potential avenues for therapeutic intervention that may be exploited for cancer immunotherapy.
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Affiliation(s)
- Mark Lawrence
- Cancer Research UK Beatson Institute, Glasgow, UK; Institute of Cancer Sciences, University of Glasgow, UK
| | - Robert Wiesheu
- Cancer Research UK Beatson Institute, Glasgow, UK; Institute of Cancer Sciences, University of Glasgow, UK
| | - Seth B Coffelt
- Cancer Research UK Beatson Institute, Glasgow, UK; Institute of Cancer Sciences, University of Glasgow, UK.
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23
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Bronte G, Petracci E, De Matteis S, Canale M, Zampiva I, Priano I, Cravero P, Andrikou K, Burgio MA, Ulivi P, Delmonte A, Crinò L. High Levels of Circulating Monocytic Myeloid-Derived Suppressive-Like Cells Are Associated With the Primary Resistance to Immune Checkpoint Inhibitors in Advanced Non-Small Cell Lung Cancer: An Exploratory Analysis. Front Immunol 2022; 13:866561. [PMID: 35493483 PMCID: PMC9043492 DOI: 10.3389/fimmu.2022.866561] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 03/18/2022] [Indexed: 12/11/2022] Open
Abstract
BackgroundImmunotherapy has become the standard of care for non-small cell lung cancer (NSCLC) patients. Some patients experience primary resistance to immunotherapy. Currently, we lack a marker of resistance to immunotherapy. Myeloid-derived suppressive-like cells (MDSCs) can reduce tumor response rate and survival outcomes.MethodsThis is an exploratory prospective observational study on metastatic NSCLC patients starting immunotherapy. Baseline peripheral blood samples were collected. Monocytic (M)-MDSCs were analyzed by flow cytometry. The main clinical outcomes were tumor response, progression-free survival (PFS), and overall survival (OS). The association between MDSC levels and tumor response was assessed. The association of PFS with OS was investigated using the Kaplan–Meier method and the Cox proportional hazards model.ResultsTwenty-two patients were included. The median M-MDSC value was higher in patients with progressive disease than patients with stable disease or partial response, p = 0.045. The median MDSC value in the overall population was 1.9. We found worse PFS (HR = 2.51; p = 0.046) and OS (HR = 2.68; p = 0.042) in patients with M-MDSC values higher than the median.ConclusionsIn this exploratory analysis, high M-MDSC levels are strongly associated with primary resistance to immunotherapy. If validated in larger studies, MDSC levels in blood samples could help to select NSCLC patients for higher benefit from immunotherapy.
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Affiliation(s)
- Giuseppe Bronte
- Department of Clinical and Molecular Sciences (DISCLIMO), Università Politecnica delle Marche, Ancona, Italy
- *Correspondence: Giuseppe Bronte,
| | - Elisabetta Petracci
- Unit of Biostatistics and Clinical Trials, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
| | - Serena De Matteis
- Unit of Immunobiology of Transplants and Advanced Cellular Therapy, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Matteo Canale
- Biosciences Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
| | - Ilaria Zampiva
- Section of Oncology, Department of Medicine, University of Verona; Centro Ricerche Cliniche di Verona (CRC), Verona, Italy
| | - Ilaria Priano
- Department of Medical Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
| | - Paola Cravero
- Department of Medical Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
| | - Kalliopi Andrikou
- Department of Medical Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
| | - Marco Angelo Burgio
- Department of Medical Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
| | - Paola Ulivi
- Biosciences Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
| | - Angelo Delmonte
- Department of Medical Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
| | - Lucio Crinò
- Department of Medical Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
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Xiong W, He W, Wang T, He S, Xu F, Wang Z, Wang X, Guo H, Ling J, Zhang H, Liu Y, Xing K, Li M, Zhang H, Li J, Niu N, Xue J, Zhan Q, Liu Z, Bei J, Huang P, Liu J, Xia L, Xia X. Smad4 Deficiency Promotes Pancreatic Cancer Immunogenicity by Activating the Cancer-Autonomous DNA-Sensing Signaling Axis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2103029. [PMID: 35064757 PMCID: PMC8895117 DOI: 10.1002/advs.202103029] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 12/03/2021] [Indexed: 06/14/2023]
Abstract
Smad4, a key mediator of the transforming growth factor-β signaling, is mutated or deleted in 20% of pancreatic ductal adenocarcinoma (PDAC) cancers and significantly affects cancer development. However, the effect of Smad4 loss on the immunogenicity and tumor immune microenvironment of PDAC is still unclear. Here, a surprising function of Smad4 in suppressing mouse PDAC tumor immunogenicity is identified. Although Smad4 deletion in tumor cells enhances proliferation in vitro, the in vivo growth of Smad4-deficient PDAC tumor is significantly inhibited on immunocompetent C57BL/6 (B6) mice, but not on immunodeficient mice or CD8+ cell-depleted B6 mice. Mechanistically, Smad4 deficiency significantly increases tumor cell immunogenicity by promoting spontaneous DNA damage and stimulating STING-mediated type I interferon signaling,which contributes to the activation of type 1 conventional dendritic cells (cDC1) and subsequent CD8+ T cells for tumor control. Furthermore, retarded tumor growth of Smad4-deficient PDAC cells on B6 mice is largely reversed when Sting is codeleted, or when the cells are implanted into interferon-alpha receptor-deficientmice or cDC1-deficientmice. Accordingly, Smad4 deficiency promotes PDAC immunogenicity by inducing tumor-intrinsic DNA damage-elicited type I interferon signaling.
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Affiliation(s)
- Wenjing Xiong
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhou510060China
| | - Wenzhuo He
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhou510060China
- VIP RegionSun Yat‐sen University Cancer CenterGuangzhou510060P. R. China
| | - Tiantian Wang
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhou510060China
| | - Shuai He
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhou510060China
| | - Feifei Xu
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhou510060China
| | - Zining Wang
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhou510060China
| | - Xiaojuan Wang
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhou510060China
| | - Hui Guo
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhou510060China
| | - Jianhua Ling
- Department of Molecular and Cellular OncologyThe University of Texas MD Anderson Cancer CenterHoustonTX77030USA
| | - Huanling Zhang
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhou510060China
| | - Yongxiang Liu
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhou510060China
| | - Kaili Xing
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhou510060China
- Department of Pancreatobiliary SurgerySun Yat‐sen University Cancer CenterGuangzhou510060P. R. China
| | - Mengyun Li
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhou510060China
| | - Hongxia Zhang
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhou510060China
| | - Jiahui Li
- College of Food Science and EngineeringDalian Polytechnic UniversityLiaoning116034P. R. China
| | - Ningning Niu
- State Key Laboratory of Oncogenes and Related GenesStem Cell Research CenterRen Ji HospitalShanghai Jiao Tong University School of MedicineShanghai200127P. R. China
| | - Jing Xue
- State Key Laboratory of Oncogenes and Related GenesStem Cell Research CenterRen Ji HospitalShanghai Jiao Tong University School of MedicineShanghai200127P. R. China
| | - Qiuyao Zhan
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhou510060China
| | - Ze‐Xian Liu
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhou510060China
| | - Jin‐Xin Bei
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhou510060China
| | - Peng Huang
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhou510060China
| | - Jinyun Liu
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhou510060China
| | - Liangping Xia
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhou510060China
- VIP RegionSun Yat‐sen University Cancer CenterGuangzhou510060P. R. China
| | - Xiaojun Xia
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhou510060China
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Li Y, Sharma A, Maciaczyk J, Schmidt-Wolf IGH. Recent Development in NKT-Based Immunotherapy of Glioblastoma: From Bench to Bedside. Int J Mol Sci 2022; 23:ijms23031311. [PMID: 35163235 PMCID: PMC8835986 DOI: 10.3390/ijms23031311] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 01/15/2022] [Accepted: 01/20/2022] [Indexed: 02/07/2023] Open
Abstract
Glioblastoma multiforme (GBM) is an aggressive and dismal disease with a median overall survival of around 15 months and a 5-year survival rate of 7.2%. Owing to genetic mutations, drug resistance, disruption to the blood–brain barrier (BBB)/blood–brain tumor barrier (BBTB), and the complexity of the immunosuppressive environment, the therapeutic approaches to GBM represent still major challenges. Conventional therapies, including surgery, radiotherapy, and standard chemotherapy with temozolomide, have not resulted in satisfactory improvements in the overall survival of GBM patients. Among cancer immunotherapeutic approaches, we propose that adjuvant NKT immunotherapy with invariant NKT (iNKT) and cytokine-induced killer (CIK) cells may improve the clinical scenario of this devastating disease. Considering this, herein, we discuss the current strategies of NKT therapy for GBM based primarily on in vitro/in vivo experiments, clinical trials, and the combinatorial approaches with future therapeutic potential.
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Affiliation(s)
- Yutao Li
- Center for Integrated Oncology (CIO), Department of Integrated Oncology, University Hospital Bonn, 53127 Bonn, Germany;
| | - Amit Sharma
- Department of Neurosurgery, University Hospital Bonn, 53127 Bonn, Germany; (A.S.); (J.M.)
| | - Jarek Maciaczyk
- Department of Neurosurgery, University Hospital Bonn, 53127 Bonn, Germany; (A.S.); (J.M.)
- Department of Surgical Sciences, University of Otago, Dunedin 9054, New Zealand
| | - Ingo G. H. Schmidt-Wolf
- Center for Integrated Oncology (CIO), Department of Integrated Oncology, University Hospital Bonn, 53127 Bonn, Germany;
- Correspondence: ; Tel.: +49-228-2871-7050
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Ma T, Renz BW, Ilmer M, Koch D, Yang Y, Werner J, Bazhin AV. Myeloid-Derived Suppressor Cells in Solid Tumors. Cells 2022; 11:cells11020310. [PMID: 35053426 PMCID: PMC8774531 DOI: 10.3390/cells11020310] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/03/2022] [Accepted: 01/11/2022] [Indexed: 12/12/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) are one of the main suppressive cell population of the immune system. They play a pivotal role in the establishment of the tumor microenvironment (TME). In the context of cancers or other pathological conditions, MDSCs can differentiate, expand, and migrate in large quantities during circulation, inhibiting the cytotoxic functions of T cells and NK cells. This process is regulated by ROS, iNOS/NO, arginase-1, and multiple soluble cytokines. The definition of MDSCs and their phenotypes in humans are not as well represented as in other organisms such as mice, owing to the absence of the cognate molecule. However, a comprehensive understanding of the differences between different species and subsets will be beneficial for clarifying the immunosuppressive properties and potential clinical values of these cells during tumor progression. Recently, experimental evidence and clinical investigations have demonstrated that MDSCs have a close relationship with poor prognosis and drug resistance, which is considered to be a leading marker for practical applications and therapeutic methods. In this review, we summarize the remarkable position of MDSCs in solid tumors, explain their classifications in different models, and introduce new treatment approaches to target MDSCs to better understand the advancement of new approaches to cancer treatment.
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Affiliation(s)
- Tianmiao Ma
- Department of General, Visceral and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany; (T.M.); (B.W.R.); (M.I.); (D.K.); (J.W.)
| | - Bernhard W. Renz
- Department of General, Visceral and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany; (T.M.); (B.W.R.); (M.I.); (D.K.); (J.W.)
- German Cancer Consortium (DKTK), Partner Site Munich, 81377 Munich, Germany
| | - Matthias Ilmer
- Department of General, Visceral and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany; (T.M.); (B.W.R.); (M.I.); (D.K.); (J.W.)
- German Cancer Consortium (DKTK), Partner Site Munich, 81377 Munich, Germany
| | - Dominik Koch
- Department of General, Visceral and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany; (T.M.); (B.W.R.); (M.I.); (D.K.); (J.W.)
| | - Yuhui Yang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China;
| | - Jens Werner
- Department of General, Visceral and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany; (T.M.); (B.W.R.); (M.I.); (D.K.); (J.W.)
- German Cancer Consortium (DKTK), Partner Site Munich, 81377 Munich, Germany
- Bavarian Cancer Research Center (BZKF), 91054 Erlangen, Germany
| | - Alexandr V. Bazhin
- Department of General, Visceral and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany; (T.M.); (B.W.R.); (M.I.); (D.K.); (J.W.)
- German Cancer Consortium (DKTK), Partner Site Munich, 81377 Munich, Germany
- Correspondence:
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Bharadwaj NS, Gumperz JE. Harnessing invariant natural killer T cells to control pathological inflammation. Front Immunol 2022; 13:998378. [PMID: 36189224 PMCID: PMC9519390 DOI: 10.3389/fimmu.2022.998378] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 08/25/2022] [Indexed: 11/13/2022] Open
Abstract
Invariant natural killer T (iNKT) cells are innate T cells that are recognized for their potent immune modulatory functions. Over the last three decades, research in murine models and human observational studies have revealed that iNKT cells can act to limit inflammatory pathology in a variety of settings. Since iNKT cells are multi-functional and can promote inflammation in some contexts, understanding the mechanistic basis for their anti-inflammatory effects is critical for effectively harnessing them for clinical use. Two contrasting mechanisms have emerged to explain the anti-inflammatory activity of iNKT cells: that they drive suppressive pathways mediated by other regulatory cells, and that they may cytolytically eliminate antigen presenting cells that promote excessive inflammatory responses. How these activities are controlled and separated from their pro-inflammatory functions remains a central question. Murine iNKT cells can be divided into four functional lineages that have either pro-inflammatory (NKT1, NKT17) or anti-inflammatory (NKT2, NKT10) cytokine profiles. However, in humans these subsets are not clearly evident, and instead most iNKT cells that are CD4+ appear oriented towards polyfunctional (TH0) cytokine production, while CD4- iNKT cells appear more predisposed towards cytolytic activity. Additionally, structurally distinct antigens have been shown to induce TH1- or TH2-biased responses by iNKT cells in murine models, but human iNKT cells may respond to differing levels of TCR stimulation in a way that does not neatly separate TH1 and TH2 cytokine production. We discuss the implications of these differences for translational efforts focused on the anti-inflammatory activity of iNKT cells.
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Affiliation(s)
- Nikhila S Bharadwaj
- Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Jenny E Gumperz
- Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
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Abstract
Gastrointestinal (GI) cancers represent a complex array of cancers that affect the digestive system. This includes liver, pancreatic, colon, rectal, anal, gastric, esophageal, intestinal and gallbladder cancer. Patients diagnosed with certain GI cancers typically have low survival rates, so new therapeutic approaches are needed. A potential approach is to harness the potent immunoregulatory properties of natural killer T (NKT) cells which are true T cells, not natural killer (NK) cells, that recognize lipid instead of peptide antigens presented by the non-classical major histocompatibility (MHC) molecule CD1d. The NKT cell subpopulation is known to play a vital role in tumor immunity by bridging innate and adaptive immune responses. In GI cancers, NKT cells can contribute to either antitumor or protumor immunity depending on the cytokine profile expressed and type of cancer. This review discusses the complexities of the role of NKT cells in liver, colon, pancreatic and gastric cancers with an emphasis on type I NKT cells.
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Affiliation(s)
- Julian Burks
- Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA,CONTACT Julian Burks National Cancer Institute, National Institute of Health, Building 41/Room D702, 41 Medlars Drive, Bethesda, Maryland20892, USA
| | - Purevdorj B. Olkhanud
- Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Jay A. Berzofsky
- Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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High TGF-β signature predicts immunotherapy resistance in gynecologic cancer patients treated with immune checkpoint inhibition. NPJ Precis Oncol 2021; 5:101. [PMID: 34921236 PMCID: PMC8683510 DOI: 10.1038/s41698-021-00242-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 11/16/2021] [Indexed: 12/13/2022] Open
Abstract
Various immune signatures predictive of resistance to immune checkpoint inhibitors (ICI) have been described in multiple solid cancers, but still under-investigated in gynecological (GYN) cancer. For 49 GYN cancer patients included in our study, without transcriptome signature, immune-related toxicity was the only clinical predictor of ICI treatment response (p = 0.008). The objective clinical response was the only predictor of progression-free survival (ICI-PFS, p = 0.0008) and overall survival (ICI-OS, p = 0.01). Commonly used ICI marker PD-L1 expression negatively correlated with progression-free survival (ICI-PFS) (p = 0.0019). We performed transcriptome and signaling pathway enrichment analyses based on ICI treatment responses and the survival outcome, and further estimated immune cell abundance using 547 gene markers. Our data revealed that TGF-β regulated signaling pathway was noted to play an important role in immunotherapy failure. Using our 6-genes TGF-β score, we observed longer ICI-PFS associated with lower TGF-β score (8.1 vs. 2.8 months, p = 0.046), which was especially more prominent in ovarian cancer (ICI-PFS 16.6 vs. 2.65 months, p = 0.0012). Further, abundant immunosuppressive cells like T-regulatory cells, eosinophils, and M2 macrophages were associated with shorter ICI-OS and correlated positively with CD274 and CTLA4 expressions. This study provides insight on the potential role of TGF-β in mediating immunotherapy resistance and cross-talking to immunosuppressive environment in GYN cancer. The TGF-β score, if validated in a larger cohort, can identify patients who likely to fail ICI and benefit from targeting this pathway to enhance the response to ICI.
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Gupta A, Budhu S, Fitzgerald K, Giese R, Michel AO, Holland A, Campesato LF, van Snick J, Uyttenhove C, Ritter G, Wolchok JD, Merghoub T. Isoform specific anti-TGFβ therapy enhances antitumor efficacy in mouse models of cancer. Commun Biol 2021; 4:1296. [PMID: 34789823 PMCID: PMC8599839 DOI: 10.1038/s42003-021-02773-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 10/04/2021] [Indexed: 11/17/2022] Open
Abstract
TGFβ is a potential target in cancer treatment due to its dual role in tumorigenesis and homeostasis. However, the expression of TGFβ and its inhibition within the tumor microenvironment has mainly been investigated in stroma-heavy tumors. Using B16 mouse melanoma and CT26 colon carcinoma as models of stroma-poor tumors, we demonstrate that myeloid/dendritic cells are the main sources of TGFβ1 and TGFβ3. Depending on local expression of TGFβ isoforms, isoform specific inhibition of either TGFβ1 or TGFβ3 may be effective. The TGFβ signature of CT26 colon carcinoma is defined by TGFβ1 and TGFβ1 inhibition results in tumor delay; B16 melanoma has equal expression of both isoforms and inhibition of either TGFβ1 or TGFβ3 controls tumor growth. Using T cell functional assays, we show that the mechanism of tumor delay is through and dependent on enhanced CD8+ T cell function. To overcome the local immunosuppressive environment, we found that combining TGFβ inhibition with immune checkpoint blockade results in improved tumor control. Our data suggest that TGFβ inhibition in stroma poor tumors shifts the local immune environment to favor tumor suppression.
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Affiliation(s)
- Aditi Gupta
- Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
- Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
| | - Sadna Budhu
- Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
- Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
| | - Kelly Fitzgerald
- Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
- Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
| | - Rachel Giese
- Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
- Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
| | - Adam O Michel
- Laboratory of Comparative Pathology, Center of Comparative Medicine and Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
| | - Aliya Holland
- Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
- Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
| | - Luis Felipe Campesato
- Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
- Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
| | | | | | - Gerd Ritter
- Ludwig Institute for Cancer Research Ltd, New York, NY, USA
| | - Jedd D Wolchok
- Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
- Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Weill Cornell Medical College, New York, NY, 10065, USA.
| | - Taha Merghoub
- Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
- Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Weill Cornell Medical College, New York, NY, 10065, USA.
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31
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Gevenois PJLY, De Pauw P, Schoonooghe S, Delporte C, Sebti T, Amighi K, Muyldermans S, Wauthoz N. Development of Neutralizing Multimeric Nanobody Constructs Directed against IL-13: From Immunization to Lead Optimization. THE JOURNAL OF IMMUNOLOGY 2021; 207:2608-2620. [PMID: 34645688 DOI: 10.4049/jimmunol.2100250] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 09/16/2021] [Indexed: 11/19/2022]
Abstract
IL-13 is a pleiotropic cytokine mainly secreted by Th2 cells. It reacts with many different types of cells involved in allergy, inflammation, and fibrosis, e.g., mastocytes, B cells, and fibroblasts. The role of IL-13 in conditions involving one or several of these phenotypes has therefore been extensively investigated. The inhibition of this cytokine in animal models for various pathologies yielded highly promising results. However, most human trials relying on anti-IL-13 conventional mAbs have failed to achieve a significant improvement of the envisaged disorders. Where some studies might have suffered from several weaknesses, the strategies themselves, such as targeting only IL-13 using conventional mAbs or employing a systemic administration, could be questioned. Nanobodies are recombinant Ag-binding fragments derived from the variable part of H chain-only Abs occurring in Camelidae. Thanks to their single-domain structure, small size (≈15 kDa), good stability, and solubility, they can be engineered into multispecific constructs for combined therapies or for use in new strategies such as formulations for local administration, e.g., pulmonary administration. In this study, we describe the generation of 38 nanobodies that can be subdivided into five CDR3 families. Nine nanobodies were found to have a good affinity profile (KD = 1-200 nM), but none were able to strongly inhibit IL-13 biological activity in vitro (IC50 > 50 µM: HEK-Blue IL-13/IL-4 cells). Multimeric constructs were therefore designed from these inhibitors and resulted in an up to 36-fold improvement in affinity and up to 300-fold enhancement of the biological activity while conserving a high specificity toward IL-13.
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Affiliation(s)
- Philippe J-L Y Gevenois
- Unit of Pharmaceutics and Biopharmaceutics, Free University of Brussels, Faculty of Pharmacy, Brussels, Belgium;
| | - Pieter De Pauw
- Laboratory of Cellular and Molecular Immunology, Free University of Brussels, Ixelles, Belgium
| | - Steve Schoonooghe
- Flemish Institute for Biotechnology Nanobody Core, Free University of Brussels, Brussels, Belgium
| | - Cédric Delporte
- Unit of Pharmacognosy, Bioanalysis and Drug Discovery, RD3 and Analytical Platform of the Faculty of Pharmacy, Free University of Brussels, Brussels, Belgium; and
| | | | - Karim Amighi
- Unit of Pharmaceutics and Biopharmaceutics, Free University of Brussels, Faculty of Pharmacy, Brussels, Belgium
| | - Serge Muyldermans
- Laboratory of Cellular and Molecular Immunology, Free University of Brussels, Ixelles, Belgium
| | - Nathalie Wauthoz
- Unit of Pharmaceutics and Biopharmaceutics, Free University of Brussels, Faculty of Pharmacy, Brussels, Belgium
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Abstract
ABSTRACT Gliomas and glioblastoma comprise the majority of brain malignancies and are difficult to treat despite standard of care and advances in immunotherapy. The challenges of controlling glioma growth and recurrence involve the uniquely immunosuppressive tumor microenvironment and systemic blunting of immune responses. In addition to highlighting key features of glioma and glioblastoma composition and immunogenicity, this review presents several future directions for immunotherapy, such as vaccines and synergistic combination treatment regimens, to better combat these tumors.
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Ni Y, Soliman A, Joehlin-Price A, Abdul-Karim F, Rose PG, Mahdi H. Immune cells and signatures characterize tumor microenvironment and predict outcome in ovarian and endometrial cancers. Immunotherapy 2021; 13:1179-1192. [PMID: 34424031 DOI: 10.2217/imt-2021-0052] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Aims: We investigated immunogenomic signatures and correlated them with survival in ovarian cancer (OV) and endometrial cancer (EC). Materials & method: We used whole transcriptome sequencing data from uterine serous cancer and The Cancer Genome Atlas data of OV and EC (n = 719). Gene expression score was calculated. Population abundance of immune cells were estimated. Results: TGF-β, myeloid cells, IFN-γ, T cells, B cells and endothelial cells predicted overall survival. Whereas CD47, neutrophils and endothelial cells predicted progression-free survival. In multivariate analyses, TGF-β, CD47 and monocytic cells predicted survival in high levels of microsatellite instability (MSI-H) EC whereas high IFN-γ trended toward improved survival in the MSI-S EC. High IFN-γ/low TGF-β and high IFN-γ/low CD47 signatures predicted longer overall survival. Low TGF-β/low CD47 signature predicted longer overall survival only in the MSI-H EC. Conclusion: Our data support the role of immune markers in predicting survival in OV/EC.
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Affiliation(s)
- Ying Ni
- Department of Quantative Health Science, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
| | - Ahmed Soliman
- Department of Pediatrics, Case Western University, 2103 Cornell Rd, Cleveland, OH 44106, USA
| | - Amy Joehlin-Price
- Department of Anatomic Pathology, Pathology & Laboratory Medicine Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
| | - Fadi Abdul-Karim
- Department of Anatomic Pathology, Pathology & Laboratory Medicine Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
| | - Peter G Rose
- Division of Gynecologic Oncology; Obstetrics, Gynecology & Women's Health Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
| | - Haider Mahdi
- Division of Gynecologic Oncology; Obstetrics, Gynecology & Women's Health Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.,Translational Hematology Oncology Research Department, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.,Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.,Magee Womens Research Institute, University of Pittsburgh, School of Medicine Gynecologic Oncology, University of Pittsburgh Medical Center, 300 Halket Street, Pittsburgh, PA 15213, USA
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34
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Li X, Li Y, Yu Q, Qian P, Huang H, Lin Y. Metabolic reprogramming of myeloid-derived suppressor cells: An innovative approach confronting challenges. J Leukoc Biol 2021; 110:257-270. [PMID: 34075637 PMCID: PMC8361984 DOI: 10.1002/jlb.1mr0421-597rr] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 04/11/2021] [Accepted: 04/12/2021] [Indexed: 02/06/2023] Open
Abstract
Immune cells such as T cells, macrophages, dendritic cells, and other immunoregulatory cells undergo metabolic reprogramming in cancer and inflammation-derived microenvironment to meet specific physiologic and functional demands. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that are characterized by immunosuppressive activity, which plays a key role in host immune homeostasis. In this review, we have discussed the core metabolic pathways, including glycolysis, lipid and fatty acid biosynthesis, and amino acid metabolism in the MDSCs under various pathologic situations. Metabolic reprogramming is a determinant of the phenotype and functions of MDSCs, and is therefore a novel therapeutic possibility in various diseases.
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Affiliation(s)
- Xiaoqing Li
- Bone Marrow Transplantation Center, the First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouZhejiangChina
- Institute of HematologyZhejiang UniversityHangzhouZhejiangChina
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity TherapyHangzhouZhejiangChina
- Liangzhu LaboratoryZhejiang University Medical CenterHangzhouZhejiangChina
| | - Yixue Li
- Bone Marrow Transplantation Center, the First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouZhejiangChina
- Institute of HematologyZhejiang UniversityHangzhouZhejiangChina
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity TherapyHangzhouZhejiangChina
- Liangzhu LaboratoryZhejiang University Medical CenterHangzhouZhejiangChina
| | - Qinru Yu
- Bone Marrow Transplantation Center, the First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouZhejiangChina
- Institute of HematologyZhejiang UniversityHangzhouZhejiangChina
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity TherapyHangzhouZhejiangChina
- Liangzhu LaboratoryZhejiang University Medical CenterHangzhouZhejiangChina
| | - Pengxu Qian
- Institute of HematologyZhejiang UniversityHangzhouZhejiangChina
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity TherapyHangzhouZhejiangChina
- Liangzhu LaboratoryZhejiang University Medical CenterHangzhouZhejiangChina
| | - He Huang
- Bone Marrow Transplantation Center, the First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouZhejiangChina
- Institute of HematologyZhejiang UniversityHangzhouZhejiangChina
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity TherapyHangzhouZhejiangChina
- Liangzhu LaboratoryZhejiang University Medical CenterHangzhouZhejiangChina
| | - Yu Lin
- Bone Marrow Transplantation Center, the First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouZhejiangChina
- Institute of HematologyZhejiang UniversityHangzhouZhejiangChina
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity TherapyHangzhouZhejiangChina
- Liangzhu LaboratoryZhejiang University Medical CenterHangzhouZhejiangChina
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35
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Regulation and Functions of Protumoral Unconventional T Cells in Solid Tumors. Cancers (Basel) 2021; 13:cancers13143578. [PMID: 34298791 PMCID: PMC8304984 DOI: 10.3390/cancers13143578] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Revised: 07/02/2021] [Accepted: 07/12/2021] [Indexed: 01/03/2023] Open
Abstract
The vast majority of studies on T cell biology in tumor immunity have focused on peptide-reactive conventional T cells that are restricted to polymorphic major histocompatibility complex molecules. However, emerging evidence indicated that unconventional T cells, including γδ T cells, natural killer T (NKT) cells and mucosal-associated invariant T (MAIT) cells are also involved in tumor immunity. Unconventional T cells span the innate-adaptive continuum and possess the unique ability to rapidly react to nonpeptide antigens via their conserved T cell receptors (TCRs) and/or to activating cytokines to orchestrate many aspects of the immune response. Since unconventional T cell lineages comprise discrete functional subsets, they can mediate both anti- and protumoral activities. Here, we review the current understanding of the functions and regulatory mechanisms of protumoral unconventional T cell subsets in the tumor environment. We also discuss the therapeutic potential of these deleterious subsets in solid cancers and why further feasibility studies are warranted.
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36
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Brettschneider EES, Terabe M. The Role of NKT Cells in Glioblastoma. Cells 2021; 10:cells10071641. [PMID: 34208864 PMCID: PMC8307781 DOI: 10.3390/cells10071641] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 06/18/2021] [Accepted: 06/25/2021] [Indexed: 12/11/2022] Open
Abstract
Glioblastoma is an aggressive and deadly cancer, but to date, immunotherapies have failed to make significant strides in improving prognoses for glioblastoma patients. One of the current challenges to developing immunological interventions for glioblastoma is our incomplete understanding of the numerous immunoregulatory mechanisms at play in the glioblastoma tumor microenvironment. We propose that Natural Killer T (NKT) cells, which are unconventional T lymphocytes that recognize lipid antigens presented by CD1d molecules, may play a key immunoregulatory role in glioblastoma. For example, evidence suggests that the activation of type I NKT cells can facilitate anti-glioblastoma immune responses. On the other hand, type II NKT cells are known to play an immunosuppressive role in other cancers, as well as to cross-regulate type I NKT cell activity, although their specific role in glioblastoma remains largely unclear. This review provides a summary of our current understanding of NKT cells in the immunoregulation of glioblastoma as well as highlights the involvement of NKT cells in other cancers and central nervous system diseases.
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Affiliation(s)
- Emily E. S. Brettschneider
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA;
- Nuffield Department of Medicine, Ludwig Institute for Cancer Research, University of Oxford, Oxford OX3 7DQ, UK
| | - Masaki Terabe
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA;
- Correspondence: ; Tel.: +1-240-760-6731
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37
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Cai J, Cui Y, Yang J, Wang S. Epithelial-mesenchymal transition: When tumor cells meet myeloid-derived suppressor cells. Biochim Biophys Acta Rev Cancer 2021; 1876:188564. [PMID: 33974950 DOI: 10.1016/j.bbcan.2021.188564] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 05/05/2021] [Accepted: 05/05/2021] [Indexed: 12/12/2022]
Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous myeloid cell population characterized by protumoral functions in the tumor immune network. An increasing number of studies have focused on the biological functions of MDSCs in tumor immunity. Epithelial-mesenchymal transition (EMT) is a cellular plasticity process accompanied by a loss of epithelial phenotypes and an acquisition of mesenchymal phenotypes. In general, tumor cells that undergo EMT are more likely to invade and metastasize. Recently, extensive evidence suggests that EMT is closely related to a highly immunosuppressive environment. This review will summarize the immunosuppressive capacities of MDSC subsets and their distinct role in tumor EMT and further discuss immunotherapy for tumor EMT by targeting MDSCs.
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Affiliation(s)
- Jingshan Cai
- Department of Laboratory Medicine, the Affiliated People's Hospital, Jiangsu University, Zhenjiang, China; Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Yudan Cui
- Department of Laboratory Medicine, the Affiliated People's Hospital, Jiangsu University, Zhenjiang, China; Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Jun Yang
- Department of Laboratory Medicine, the Affiliated People's Hospital, Jiangsu University, Zhenjiang, China.
| | - Shengjun Wang
- Department of Laboratory Medicine, the Affiliated People's Hospital, Jiangsu University, Zhenjiang, China; Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China.
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38
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Baumeister T, Ingermann J, Marcazzan S, Fang HY, Oellinger R, Rad R, Engleitner T, Kleigrewe K, Anand A, Strangmann J, Schmid RM, Wang TC, Quante M. Anti-inflammatory chemoprevention attenuates the phenotype in a mouse model of esophageal adenocarcinoma. Carcinogenesis 2021; 42:1068-1078. [PMID: 33878160 DOI: 10.1093/carcin/bgab032] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 01/29/2021] [Accepted: 04/16/2021] [Indexed: 01/20/2023] Open
Abstract
Barrett´s Esophagus (BE) is the main known precursor condition of Esophageal Adenocarcinoma (EAC). BE is defined by the presence of metaplasia above the normal squamous columnar junction and has mainly been attributed to gastroesophageal reflux disease (GERD) and chronic reflux esophagitis. Thus, the rising incidence of EAC in the Western world is likely mediated by chronic esophageal inflammation, secondary to GERD in combination with environmental risk factors such as a Western diet and obesity. However, (at present) risk prediction tools and endoscopic surveillance have shown limited effectiveness. Chemoprevention as an adjunctive approach remains an attractive option to reduce the incidence of neoplastic disease. Here, we investigate the feasibility of chemopreventive approaches in BE and EAC via inhibition of inflammatory signaling in a transgenic mouse model of BE and EAC (L2-IL1B mice), with accelerated tumor formation on a high fat diet (HFD). L2-IL1B mice were treated with the IL-1 receptor antagonist Anakinra and the nonsteroidal anti-inflammatory drugs (NSAIDs) aspirin or Sulindac. Interleukin-1b antagonism reduced tumor progression in L2-IL1B mice with or without a HFD, while both NSAIDs were effective chemoprevention agents in the accelerated HFD fed L2-IL1B mouse model. Sulindac treatment also resulted in a marked change in the immune profile of L2-IL-1B mice. In summary, anti-inflammatory treatment of HFD-treated L2-IL1B mice acted protectively on disease progression. These results from a mouse model of BE support results from clinical trials that suggest that anti-inflammatory medication may be effective in the chemoprevention of EAC.
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Affiliation(s)
- Theresa Baumeister
- Department of Medicine II, Klinikum rechts der Isar, Technical University Munich (TUM), Ismaninger Str, München, Germany
| | - Jonas Ingermann
- Department of Medicine II, Klinikum rechts der Isar, Technical University Munich (TUM), Ismaninger Str, München, Germany
| | - Sabrina Marcazzan
- Department of Medicine II, Klinikum rechts der Isar, Technical University Munich (TUM), Ismaninger Str, München, Germany
| | - Hsin-Yu Fang
- Department of Medicine II, Klinikum rechts der Isar, Technical University Munich (TUM), Ismaninger Str, München, Germany
| | - Rupert Oellinger
- Institute of Molecular Oncology and Functional Genomics, Klinikum rechts der Isar, Technical University Munich (TUM), Ismaninger Str, München, Germany
| | - Roland Rad
- Department of Medicine II, Klinikum rechts der Isar, Technical University Munich (TUM), Ismaninger Str, München, Germany.,Institute of Molecular Oncology and Functional Genomics, Klinikum rechts der Isar, Technical University Munich (TUM), Ismaninger Str, München, Germany
| | - Thomas Engleitner
- Institute of Molecular Oncology and Functional Genomics, Klinikum rechts der Isar, Technical University Munich (TUM), Ismaninger Str, München, Germany
| | - Karin Kleigrewe
- Leibniz-Institute for Food Systems Biology at the Technical University of Munich
| | - Akanksha Anand
- Department of Medicine II, Klinikum rechts der Isar, Technical University Munich (TUM), Ismaninger Str, München, Germany
| | - Julia Strangmann
- Department of Medicine II, Klinikum rechts der Isar, Technical University Munich (TUM), Ismaninger Str, München, Germany
| | - Roland M Schmid
- Department of Medicine II, Klinikum rechts der Isar, Technical University Munich (TUM), Ismaninger Str, München, Germany
| | - Timothy C Wang
- Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Michael Quante
- Department of Medicine II, Klinikum rechts der Isar, Technical University Munich (TUM), Ismaninger Str, München, Germany.,Innere Medizin II, Universitätskliniken Freiburg, Universität Freiburg, Germany
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39
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Chuntova P, Chow F, Watchmaker PB, Galvez M, Heimberger AB, Newell EW, Diaz A, DePinho RA, Li MO, Wherry EJ, Mitchell D, Terabe M, Wainwright DA, Berzofsky JA, Herold-Mende C, Heath JR, Lim M, Margolin KA, Chiocca EA, Kasahara N, Ellingson BM, Brown CE, Chen Y, Fecci PE, Reardon DA, Dunn GP, Liau LM, Costello JF, Wick W, Cloughesy T, Timmer WC, Wen PY, Prins RM, Platten M, Okada H. Unique challenges for glioblastoma immunotherapy-discussions across neuro-oncology and non-neuro-oncology experts in cancer immunology. Meeting Report from the 2019 SNO Immuno-Oncology Think Tank. Neuro Oncol 2021; 23:356-375. [PMID: 33367885 PMCID: PMC7992879 DOI: 10.1093/neuonc/noaa277] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Cancer immunotherapy has made remarkable advances with over 50 separate Food and Drug Administration (FDA) approvals as first- or second-line indications since 2015. These include immune checkpoint blocking antibodies, chimeric antigen receptor-transduced T cells, and bispecific T-cell-engaging antibodies. While multiple cancer types now benefit from these immunotherapies, notable exceptions thus far include brain tumors, such as glioblastoma. As such, it seems critical to gain a better understanding of unique mechanistic challenges underlying the resistance of malignant gliomas to immunotherapy, as well as to acquire insights into the development of future strategies. An Immuno-Oncology Think Tank Meeting was held during the 2019 Annual Society for Neuro-Oncology Scientific Conference. Discussants in the fields of neuro-oncology, neurosurgery, neuro-imaging, medical oncology, and cancer immunology participated in the meeting. Sessions focused on topics such as the tumor microenvironment, myeloid cells, T-cell dysfunction, cellular engineering, and translational aspects that are critical and unique challenges inherent with primary brain tumors. In this review, we summarize the discussions and the key messages from the meeting, which may potentially serve as a basis for advancing the field of immune neuro-oncology in a collaborative manner.
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Affiliation(s)
- Pavlina Chuntova
- Department of Neurological Surgery, UCSF, San Francisco, California
| | - Frances Chow
- Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California
| | | | - Mildred Galvez
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, Los Angeles, California
| | - Amy B Heimberger
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Evan W Newell
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Aaron Diaz
- Department of Neurological Surgery, UCSF, San Francisco, California
| | - Ronald A DePinho
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ming O Li
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - E John Wherry
- Department of Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Duane Mitchell
- Department of Neurosurgery, University of Florida College of Medicine, Gainesville, Florida
| | - Masaki Terabe
- Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Derek A Wainwright
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Jay A Berzofsky
- Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | | | | | - Michael Lim
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Kim A Margolin
- Department of Medical Oncology & Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, California
| | - E Antonio Chiocca
- Department of Neurosurgery, Brigham and Women's Hospital, Boston, Massachusetts
| | | | - Benjamin M Ellingson
- Department of Radiological Sciences, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Christine E Brown
- Department of Immuno-Oncology, Beckman Research Institute of the City of Hope, Duarte, California
| | - Yvonne Chen
- Department of Microbiology, Immunology & Molecular Genetics, UCLA, Los Angeles, California
| | - Peter E Fecci
- Department of Neurosurgery, Duke University School of Medicine, Durham, North Carolina
| | - David A Reardon
- Department of Medicine/Medical Oncology, Harvard Medical School, Boston, Massachusetts
| | - Gavin P Dunn
- Department of Neurological Surgery, Washington University School of Medicine, St. Louis, Missouri
| | - Linda M Liau
- Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, California
| | | | - Wolfgang Wick
- Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany
| | - Timothy Cloughesy
- Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - William C Timmer
- Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland
| | - Patrick Y Wen
- Center for Neuro-Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Robert M Prins
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, Los Angeles, California.,Parker Institute for Cancer Immunotherapy, San Francisco, California
| | - Michael Platten
- Department of Neurology, Medical Faculty Mannheim, MCTN, University of Heidelberg, Mannheim, Germany.,DKTK CCU Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Hideho Okada
- Department of Neurological Surgery, UCSF, San Francisco, California.,Parker Institute for Cancer Immunotherapy, San Francisco, California
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40
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Dorhoi A, Kotzé LA, Berzofsky JA, Sui Y, Gabrilovich DI, Garg A, Hafner R, Khader SA, Schaible UE, Kaufmann SH, Walzl G, Lutz MB, Mahon RN, Ostrand-Rosenberg S, Bishai W, du Plessis N. Therapies for tuberculosis and AIDS: myeloid-derived suppressor cells in focus. J Clin Invest 2021; 130:2789-2799. [PMID: 32420917 DOI: 10.1172/jci136288] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The critical role of suppressive myeloid cells in immune regulation has come to the forefront in cancer research, with myeloid-derived suppressor cells (MDSCs) as a main oncology immunotherapeutic target. Recent improvement and standardization of criteria classifying tumor-induced MDSCs have led to unified descriptions and also promoted MDSC research in tuberculosis (TB) and AIDS. Despite convincing evidence on the induction of MDSCs by pathogen-derived molecules and inflammatory mediators in TB and AIDS, very little attention has been given to their therapeutic modulation or roles in vaccination in these diseases. Clinical manifestations in TB are consequences of complex host-pathogen interactions and are substantially affected by HIV infection. Here we summarize the current understanding and knowledge gaps regarding the role of MDSCs in HIV and Mycobacterium tuberculosis (co)infections. We discuss key scientific priorities to enable application of this knowledge to the development of novel strategies to improve vaccine efficacy and/or implementation of enhanced treatment approaches. Building on recent findings and potential for cross-fertilization between oncology and infection biology, we highlight current challenges and untapped opportunities for translating new advances in MDSC research into clinical applications for TB and AIDS.
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Affiliation(s)
- Anca Dorhoi
- Institute of Immunology, Friedrich-Loeffler-Institute, Greifswald-Insel Riems, Germany.,Faculty of Mathematics and Natural Sciences, University of Greifswald, Greifswald, Germany
| | - Leigh A Kotzé
- Centre for Tuberculosis Research, South African Medical Research Council, Cape Town, South Africa.,DST-NRF Centre of Excellence for Biomedical Tuberculosis Research (CBTBR) and.,Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Jay A Berzofsky
- Vaccine Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA
| | - Yongjun Sui
- Vaccine Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA
| | | | - Ankita Garg
- Department of Infectious Diseases, University of Georgia, Athens, Georgia, USA
| | - Richard Hafner
- Division of AIDS, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA
| | - Shabaana A Khader
- Department of Molecular Microbiology, Washington University in St. Louis, St. Louis, Missouri, USA
| | - Ulrich E Schaible
- Cellular Microbiology, Priority Program Infections.,Thematic Translation Unit Tuberculosis, German Center for Infection Research, and.,Leibniz Research Alliance INFECTIONS'21, Research Center Borstel, Borstel, Germany
| | - Stefan He Kaufmann
- Max Planck Institute for Infection Biology, Berlin, Germany.,Hagler Institute for Advanced Study, Texas A&M University, College Station, Texas, USA
| | - Gerhard Walzl
- Centre for Tuberculosis Research, South African Medical Research Council, Cape Town, South Africa.,DST-NRF Centre of Excellence for Biomedical Tuberculosis Research (CBTBR) and.,Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Manfred B Lutz
- Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany
| | - Robert N Mahon
- Division of AIDS, Columbus Technologies & Services Inc., Contractor to National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA
| | - Suzanne Ostrand-Rosenberg
- Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA
| | - William Bishai
- Center for Tuberculosis Research, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Nelita du Plessis
- Centre for Tuberculosis Research, South African Medical Research Council, Cape Town, South Africa.,DST-NRF Centre of Excellence for Biomedical Tuberculosis Research (CBTBR) and.,Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
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41
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Shen H, Gu C, Liang T, Liu H, Guo F, Liu X. Unveiling the heterogeneity of NKT cells in the liver through single cell RNA sequencing. Sci Rep 2020; 10:19453. [PMID: 33173202 PMCID: PMC7655820 DOI: 10.1038/s41598-020-76659-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Accepted: 10/29/2020] [Indexed: 11/10/2022] Open
Abstract
CD1d-dependent type I NKT cells, which are activated by lipid antigen, are known to play important roles in innate and adaptive immunity, as are a portion of type II NKT cells. However, the heterogeneity of NKT cells, especially NKT-like cells, remains largely unknown. Here, we report the profiling of NKT (NK1.1+CD3e+) cells in livers from wild type (WT), Jα18-deficient and CD1d-deficient mice by single-cell RNA sequencing. Unbiased transcriptional clustering revealed distinct cell subsets. The transcriptomic profiles identified the well-known CD1d-dependent NKT cells and defined two CD1d-independent NKT cell subsets. In addition, validation of marker genes revealed the differential organ distribution and landscape of NKT cell subsets during liver tumor progression. More importantly, we found that CD1d-independent Sca-1−CD62L+ NKT cells showed a strong ability to secrete IFN-γ after costimulation with IL-2, IL-12 and IL-18 in vitro. Collectively, our findings provide a comprehensive characterization of NKT cell heterogeneity and unveil a previously undefined functional NKT cell subset.
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Affiliation(s)
- Hao Shen
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Chan Gu
- Center for Translational Medicine, Ministry of Education Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Obstetrics and Gynecology, West China Second Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Tao Liang
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Haifeng Liu
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Fan Guo
- Center for Translational Medicine, Ministry of Education Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Obstetrics and Gynecology, West China Second Hospital, Sichuan University, Chengdu, 610041, Sichuan, China. .,Ministry of Education Key Laboratory of Bio-Resource and Eco-Environment, College of Life Sciences, Sichuan University, Chengdu, 610041, Sichuan, China.
| | - Xiaolong Liu
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beijing, China. .,School of Life Sciences, Hangzhou Institute for Advanced Study, UCAS, Hangzhou, 310024, China. .,School of Life Science and Technology, ShanghaiTech University, Shanghai, 200031, China.
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Lundh S, Jung IY, Dimitri A, Vora A, Melenhorst JJ, Jadlowsky JK, Fraietta JA. Clinical practice: chimeric antigen receptor (CAR) T cells: a major breakthrough in the battle against cancer. Clin Exp Med 2020; 20:469-480. [PMID: 32333215 PMCID: PMC11413805 DOI: 10.1007/s10238-020-00628-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Accepted: 04/07/2020] [Indexed: 12/16/2022]
Abstract
Chimeric antigen receptor (CAR) T cell therapy has come of age, offering a potentially curative option for patients who are refractory to standard anti-cancer treatments. The success of CAR T cell therapy in the setting of acute lymphoblastic leukemia and specific types of B cell lymphoma led to rapid regulatory approvals of CD19-directed CAR T cells, first in the United States and subsequently across the globe. Despite these major milestones in the field of immuno-oncology, growing experience with CAR T cells has also highlighted the major limitations of this strategy, namely challenges associated with manufacturing a bespoke patient-specific product, intrinsic immune cell defects leading to poor CAR T cell function as well as persistence, and/or tumor cell resistance resulting from loss or modulation of the targeted antigen. In addition, both on- and off-tumor immunotoxicities and the financial burden inherent in conventional cellular biomanufacturing often hamper the success of CAR T cell-based treatment approaches. Herein, we provide an overview of the opportunities and challenges related to the first form of gene transfer therapy to gain commercial approval in the United States. Ongoing advances in the areas of genetic engineering, precision genome editing, toxicity mitigation methods and cell manufacturing will improve the efficacy and safety of CAR T cells for hematologic malignancies and expand the use of this novel class of therapeutics to reach solid tumors.
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Affiliation(s)
- Stefan Lundh
- Center for Cellular Immunotherapies, University of Pennsylvania, South Pavilion Expansion, Room 9-104, 3400 Civic Center Blvd., Bldg. 421, Philadelphia, PA, 19104, USA
| | - In-Young Jung
- Center for Cellular Immunotherapies, University of Pennsylvania, South Pavilion Expansion, Room 9-104, 3400 Civic Center Blvd., Bldg. 421, Philadelphia, PA, 19104, USA
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Alexander Dimitri
- Center for Cellular Immunotherapies, University of Pennsylvania, South Pavilion Expansion, Room 9-104, 3400 Civic Center Blvd., Bldg. 421, Philadelphia, PA, 19104, USA
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Anish Vora
- Center for Cellular Immunotherapies, University of Pennsylvania, South Pavilion Expansion, Room 9-104, 3400 Civic Center Blvd., Bldg. 421, Philadelphia, PA, 19104, USA
| | - J Joseph Melenhorst
- Center for Cellular Immunotherapies, University of Pennsylvania, South Pavilion Expansion, Room 9-104, 3400 Civic Center Blvd., Bldg. 421, Philadelphia, PA, 19104, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA
- Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA, USA
| | - Julie K Jadlowsky
- Center for Cellular Immunotherapies, University of Pennsylvania, South Pavilion Expansion, Room 9-104, 3400 Civic Center Blvd., Bldg. 421, Philadelphia, PA, 19104, USA
| | - Joseph A Fraietta
- Center for Cellular Immunotherapies, University of Pennsylvania, South Pavilion Expansion, Room 9-104, 3400 Civic Center Blvd., Bldg. 421, Philadelphia, PA, 19104, USA.
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
- Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA, USA.
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Modulation of Immune Infiltration of Ovarian Cancer Tumor Microenvironment by Specific Subpopulations of Fibroblasts. Cancers (Basel) 2020; 12:cancers12113184. [PMID: 33138184 PMCID: PMC7692816 DOI: 10.3390/cancers12113184] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 10/20/2020] [Accepted: 10/24/2020] [Indexed: 12/15/2022] Open
Abstract
Tumor immune infiltration plays a key role in the progression of solid tumors, including ovarian cancer, and immunotherapies are rapidly emerging as effective treatment modalities. However, the role of cancer-associated fibroblasts (CAFs), a predominant stromal constituent, in determining the tumor-immune microenvironment and modulating efficacy of immunotherapies remains poorly understood. We have conducted an extensive bioinformatic analysis of our and other publicly available ovarian cancer datasets (GSE137237, GSE132289 and GSE71340), to determine the correlation of fibroblast subtypes within the tumor microenvironment (TME) with the characteristics of tumor-immune infiltration. We identified (1) four functional modules of CAFs in ovarian cancer that are associated with the TME and metastasis of ovarian cancer, (2) immune-suppressive function of the collagen 1,3,5-expressing CAFs in primary ovarian cancer and omental metastases, and (3) consistent positive correlations between the functional modules of CAFs with anti-immune response genes and negative correlation with pro-immune response genes. Our study identifies a specific fibroblast subtype, fibroblast functional module (FFM)2, in the ovarian cancer tumor microenvironment that can potentially modulate a tumor-promoting immune microenvironment, which may be detrimental toward the effectiveness of ovarian cancer immunotherapies.
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Wu H, Li SS, Zhou M, Jiang AN, He Y, Wang S, Yang W, Liu H. Palliative Radiofrequency Ablation Accelerates the Residual Tumor Progression Through Increasing Tumor-Infiltrating MDSCs and Reducing T-Cell-Mediated Anti-Tumor Immune Responses in Animal Model. Front Oncol 2020; 10:1308. [PMID: 33014771 PMCID: PMC7498645 DOI: 10.3389/fonc.2020.01308] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 06/23/2020] [Indexed: 12/12/2022] Open
Abstract
Previous studies showed that radiofrequency ablation (RFA) has a favorable treatment efficacy for hepatocellular carcinoma (HCC) or colorectal liver metastases (CRLMs). Palliative RFA (pRFA) resulting from larger HCC or multiple CRLMs further accelerated the progression of potential residual tumor, yet its mechanism was still unknown. This study investigated the influence of myeloid-derived suppressor cells (MDSCs) on T-cell immune responses and tumor recurrence after pRFA. CT26 tumor models were used. The percentage of MDSCs in peripheral blood was analyzed by flow cytometry after pRFA. The level of Th1 and Th2 cytokines were measured by ELISA through different treatments (n = 4/group). The tumor-infiltrating MDSCs, dendritic cells, and intracellular cytokines level were analyzed by IHC staining after different treatments. The functional CD8+ T cells were confirmed by the co-localization immunofluorescence staining. The long-term outcomes were also evaluated through CT26 and 4T1 tumor models. The results showed that tumor models treated with pRFA displayed significant increases in the percentage of MDSCs of peripheral blood and tumor infiltration. The expression level of TGF-β and IL-6 after pRFA was higher than that before pRFA by ELISA and IHC staining. After depleting MDSCs by combining with Abs, the pRFA + Abs group achieved a higher level of Th1 cytokines and greatly enhanced the percentage of tumor-infiltrating functional CD8+ T cells when compared with pRFA alone. The depletion of MDSCs through combination with Abs also resulted in tumor regression. In conclusion, pRFA accelerates the residual tumor progression through increasing tumor-infiltrating MDSCs and reducing T-cell-mediated anti-tumor immune responses, which could provide a potential approach for delaying tumor recurrence caused by pRFA.
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Affiliation(s)
- Hao Wu
- Department of Ultrasound, Institute of Ultrasound in Musculoskeletal Sports Medicine, Guangdong Second Provincial General Hospital, Southern Medical University, Guangzhou, China
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Ultrasound, Peking University Cancer Hospital & Institute, Beijing, China
| | - Su-shu Li
- Department of Ultrasound, Institute of Ultrasound in Musculoskeletal Sports Medicine, Guangdong Second Provincial General Hospital, Southern Medical University, Guangzhou, China
| | - Meijun Zhou
- Department of Ultrasound, Institute of Ultrasound in Musculoskeletal Sports Medicine, Guangdong Second Provincial General Hospital, Southern Medical University, Guangzhou, China
| | - An-Na Jiang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Ultrasound, Peking University Cancer Hospital & Institute, Beijing, China
| | - Yanni He
- Department of Ultrasound, Institute of Ultrasound in Musculoskeletal Sports Medicine, Guangdong Second Provincial General Hospital, Southern Medical University, Guangzhou, China
| | - Song Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Ultrasound, Peking University Cancer Hospital & Institute, Beijing, China
| | - Wei Yang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Ultrasound, Peking University Cancer Hospital & Institute, Beijing, China
| | - Hongmei Liu
- Department of Ultrasound, Institute of Ultrasound in Musculoskeletal Sports Medicine, Guangdong Second Provincial General Hospital, Southern Medical University, Guangzhou, China
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Cersosimo F, Lonardi S, Bernardini G, Telfer B, Mandelli GE, Santucci A, Vermi W, Giurisato E. Tumor-Associated Macrophages in Osteosarcoma: From Mechanisms to Therapy. Int J Mol Sci 2020; 21:E5207. [PMID: 32717819 PMCID: PMC7432207 DOI: 10.3390/ijms21155207] [Citation(s) in RCA: 148] [Impact Index Per Article: 29.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 07/20/2020] [Accepted: 07/21/2020] [Indexed: 12/20/2022] Open
Abstract
Osteosarcomas (OSs) are bone tumors most commonly found in pediatric and adolescent patients characterized by high risk of metastatic progression and recurrence after therapy. Effective therapeutic management of this disease still remains elusive as evidenced by poor patient survival rates. To achieve a more effective therapeutic management regimen, and hence patient survival, there is a need to identify more focused targeted therapies for OSs treatment in the clinical setting. The role of the OS tumor stroma microenvironment plays a significant part in the development and dissemination of this disease. Important components, and hence potential targets for treatment, are the tumor-infiltrating macrophages that are known to orchestrate many aspects of OS stromal signaling and disease progression. In particular, increased infiltration of M2-like tumor-associated macrophages (TAMs) has been associated with OS metastasis and poor patient prognosis despite currently used aggressive therapies regimens. This review aims to provide a summary update of current macrophage-centered knowledge and to discuss the possible roles that macrophages play in the process of OS metastasis development focusing on the potential influence of stromal cross-talk signaling between TAMs, cancer-stem cells and additional OSs tumoral microenvironment factors.
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Affiliation(s)
- Francesca Cersosimo
- Department of Biotechnology Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy; (F.C.); (G.B.); (A.S.)
| | - Silvia Lonardi
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (S.L.); (G.E.M.); (W.V.)
| | - Giulia Bernardini
- Department of Biotechnology Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy; (F.C.); (G.B.); (A.S.)
| | - Brian Telfer
- Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, UK;
| | - Giulio Eugenio Mandelli
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (S.L.); (G.E.M.); (W.V.)
| | - Annalisa Santucci
- Department of Biotechnology Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy; (F.C.); (G.B.); (A.S.)
| | - William Vermi
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (S.L.); (G.E.M.); (W.V.)
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Emanuele Giurisato
- Department of Biotechnology Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy; (F.C.); (G.B.); (A.S.)
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, UK
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Yang Y, Li C, Liu T, Dai X, Bazhin AV. Myeloid-Derived Suppressor Cells in Tumors: From Mechanisms to Antigen Specificity and Microenvironmental Regulation. Front Immunol 2020; 11:1371. [PMID: 32793192 PMCID: PMC7387650 DOI: 10.3389/fimmu.2020.01371] [Citation(s) in RCA: 160] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 05/28/2020] [Indexed: 12/14/2022] Open
Abstract
Among the various immunological and non-immunological tumor-promoting activities of myeloid-derived suppressor cells (MDSCs), their immunosuppressive capacity remains a key hallmark. Effort in the past decade has provided us with a clearer view of the suppressive nature of MDSCs. More suppressive pathways have been identified, and their recognized targets have been expanded from T cells and natural killer (NK) cells to other immune cells. These novel mechanisms and targets afford MDSCs versatility in suppressing both innate and adaptive immunity. On the other hand, a better understanding of the regulation of their development and function has been unveiled. This intricate regulatory network, consisting of tumor cells, stromal cells, soluble mediators, and hostile physical conditions, reveals bi-directional crosstalk between MDSCs and the tumor microenvironment. In this article, we will review available information on how MDSCs exert their immunosuppressive function and how they are regulated in the tumor milieu. As MDSCs are a well-established obstacle to anti-tumor immunity, new insights in the potential synergistic combination of MDSC-targeted therapy and immunotherapy will be discussed.
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Affiliation(s)
- Yuhui Yang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chunyan Li
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Province Key Lab of Molecular Imaging, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tao Liu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaofang Dai
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Alexandr V Bazhin
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
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Plasticity in Ovarian Cancer: The Molecular Underpinnings and Phenotypic Heterogeneity. J Indian Inst Sci 2020. [DOI: 10.1007/s41745-020-00174-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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Chulpanova DS, Kitaeva KV, Green AR, Rizvanov AA, Solovyeva VV. Molecular Aspects and Future Perspectives of Cytokine-Based Anti-cancer Immunotherapy. Front Cell Dev Biol 2020; 8:402. [PMID: 32582698 PMCID: PMC7283917 DOI: 10.3389/fcell.2020.00402] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Accepted: 05/01/2020] [Indexed: 12/11/2022] Open
Abstract
Cytokine-based immunotherapy is a promising field in the cancer treatment, since cytokines, as proteins of the immune system, are able to modulate the host immune response toward cancer cell, as well as directly induce tumor cell death. Since a low dose monotherapy with some cytokines has no significant therapeutic results and a high dose treatment leads to a number of side effects caused by the pleiotropic effect of cytokines, the problem of understanding the influence of cytokines on the immune cells involved in the pro- and anti-tumor immune response remains a pressing one. Immune system cells carry CD makers on their surface which can be used to identify various populations of cells of the immune system that play different roles in pro- and anti-tumor immune responses. This review discusses the functions and specific CD markers of various immune cell populations which are reported to participate in the regulation of the immune response against the tumor. The results of research studies and clinical trials investigating the effect of cytokine therapy on the regulation of immune cell populations and their surface markers are also discussed. Current trends in the development of cancer immunotherapy, as well as the role of cytokines in combination with other therapeutic agents, are also discussed.
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Affiliation(s)
- Daria S Chulpanova
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Kristina V Kitaeva
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Andrew R Green
- Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham Biodiscovery Institute, Nottingham, United Kingdom
| | - Albert A Rizvanov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia.,Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham Biodiscovery Institute, Nottingham, United Kingdom
| | - Valeriya V Solovyeva
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
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49
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He J, Yin P, Xu K. Effect and Molecular Mechanisms of Traditional Chinese Medicine on Tumor Targeting Tumor-Associated Macrophages. Drug Des Devel Ther 2020; 14:907-919. [PMID: 32184560 PMCID: PMC7053810 DOI: 10.2147/dddt.s223646] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Accepted: 02/05/2020] [Indexed: 12/17/2022] Open
Abstract
Traditional Chinese medicine (TCM) has been used as a significant cancer treatment method for many years in China. It has been demonstrated that TCM could assist in inhibiting the growth of tumors and prolonging the survival rates of cancer patients. Although the mechanism of TCM are still not clear, accumulating evidence has shown that they may be related to the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) play a significant role in TME and are polarized to two phenotypes, M1 (classically activated) and M2 (alternatively activated) TAMs. The two different phenotypes of TAMs play converse roles in the TME and M2-polarized tumor-associated macrophages (M2-TAMs) always lead to poor prognosis in cancer patients compared to M1-polarized tumor-associated macrophages (M1-TAMs). In this review, the potential correlation between TCM and TAMs (especially the M2 phenotype) in tumor progression and promising TCM strategies targeting TAMs in cancer are discussed.
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Affiliation(s)
- Jing He
- Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Peihao Yin
- Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
- Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
- Shanghai Putuo Central School of Clinical Medicine, Anhui Medicine University, Anhui, People’s Republic of China
- Interventional Cancer Institute of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China
| | - Ke Xu
- Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
- Shanghai Putuo Central School of Clinical Medicine, Anhui Medicine University, Anhui, People’s Republic of China
- Interventional Cancer Institute of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China
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50
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Dixon GA, Pérez CA. Multiple Sclerosis and the Choroid Plexus: Emerging Concepts of Disease Immunopathophysiology. Pediatr Neurol 2020; 103:65-75. [PMID: 31780202 DOI: 10.1016/j.pediatrneurol.2019.08.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2019] [Revised: 08/11/2019] [Accepted: 08/15/2019] [Indexed: 12/18/2022]
Abstract
BACKGROUND The coexistence of multiple sclerosis and intracranial neoplasms is very rare, and whether this occurrence can be explained by a causal relationship or by coincidence remains a matter of debate. Possible roles of the choroid plexus as a site of tumor cell invasion and lymphocyte infiltration into the central nervous system have been hypothesized in recent studies. METHODS We describe a 13-year-old boy with concurrent multiple sclerosis and choroid plexus papilloma, then review the published literature with a focus on the pathophysiologic mechanisms of neuroinflammation in multiple sclerosis and the potential role of the choroid plexus in this process. RESULTS A growing body of evidence suggests that both physical and functional dysregulation of the choroid plexus may be a common mechanism underlying the pathophysiology of central nervous system inflammation. CONCLUSIONS In multiple sclerosis, the choroid plexus could act as a gateway for lymphocyte entry from the peripheral blood into the central nervous system at its earlier stages. However, future studies are needed to identify whether structural alterations of the choroid plexus play a role in the pathophysiology of multiple sclerosis and to provide suitable models to determine their consequences.
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Affiliation(s)
- Grant A Dixon
- McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas
| | - Carlos A Pérez
- Division of Multiple Sclerosis and Neuroimmunology, Department of Neurology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas.
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