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1
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Fu Y, Chen J, Zhu X, Ding M, Wang H, Fu S. Roles and therapeutic potential of the SLC family in prostate cancer-literature review. BMC Urol 2025; 25:32. [PMID: 39966814 PMCID: PMC11837367 DOI: 10.1186/s12894-025-01714-w] [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: 10/01/2024] [Accepted: 02/10/2025] [Indexed: 02/20/2025] Open
Abstract
Prostate cancer (PCa) is one of the most common malignancies in men worldwide. Despite advances in treatment, many patients develop resistance to conventional therapies. Solute carrier (SLC) proteins, as transmembrane transporters, have recently emerged as potential therapeutic targets due to their role in tumor metabolism and progression. This review summarizes the key roles of six SLC proteins in PCa, including their involvement in metabolic reprogramming, regulation of signaling pathways, and effects on the tumor microenvironment. Although targeting of SLC family members in prostate cancer remains an underexplored area, the growing body of evidence suggests that it holds potential for future development.
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Affiliation(s)
- Yuanzhi Fu
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Wuhua District, Kunming, 650101, Yunnan, China
- Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Junhao Chen
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Wuhua District, Kunming, 650101, Yunnan, China
| | - Xingcheng Zhu
- Department of Clinical Laboratory, The Second People's Hospital of Qujing City Qujing, Yunnan, China
| | - Mingxia Ding
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Wuhua District, Kunming, 650101, Yunnan, China
| | - Haifeng Wang
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Wuhua District, Kunming, 650101, Yunnan, China.
| | - Shi Fu
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Wuhua District, Kunming, 650101, Yunnan, China.
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Emamalipour M, Shamdani S, Mansoori B, Uzan G, Naserian S. The implications of the TNFα-TNFR2 immune checkpoint signaling pathway in cancer treatment: From immunoregulation to angiogenesis. Int J Cancer 2025; 156:7-19. [PMID: 39140321 DOI: 10.1002/ijc.35130] [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: 09/13/2023] [Revised: 07/09/2024] [Accepted: 07/12/2024] [Indexed: 08/15/2024]
Abstract
Despite the tremendous advances that have been made in biomedical research, cancer remains one of the leading causes of death worldwide. Several therapeutic approaches have been suggested and applied to treat cancer with impressive results. Immunotherapy based on targeting immune checkpoint signaling pathways proved to be one of the most efficient. In this review article, we will focus on the recently discovered TNFα-TNFR2 signaling pathway, which controls the immunological and pro-angiogenic properties of many immunoregulatory and pro-angiogenic cells such as endothelial progenitor cells (EPCs), mesenchymal stem cells (MSCs), and regulatory T cells (Tregs). Due to their biological properties, these cells can play a major role in cancer progression and metastasis. Therefore, we will discuss the advantages and disadvantages of an anti-TNFR2 treatment that could carry two faces under one hood. It interrupts the immunosuppressive and pro-angiogenic behaviors of the above-mentioned cells and interferes with tumor growth and survival.
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Affiliation(s)
| | - Sara Shamdani
- CellMedEx, Saint Maur Des Fossés, France
- INSERM UMR-S-MD 1197, Hôpital Paul Brousse, Villejuif, France
| | - Behzad Mansoori
- The Wistar Institute, Molecular & Cellular Oncogenesis Program, Philadelphia, Pennsylvania, USA
| | - Georges Uzan
- INSERM UMR-S-MD 1197, Hôpital Paul Brousse, Villejuif, France
| | - Sina Naserian
- CellMedEx, Saint Maur Des Fossés, France
- INSERM UMR-S-MD 1197, Hôpital Paul Brousse, Villejuif, France
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Debesset A, Pilon C, Meunier S, Cuelenaere-Bonizec O, Richer W, Thiolat A, Houppe C, Ponzo M, Magnan J, Caron J, Caudana P, Tosello Boari J, Baulande S, To NH, Salomon BL, Piaggio E, Cascone I, Cohen JL. TNFR2 blockade promotes antitumoral immune response in PDAC by targeting activated Treg and reducing T cell exhaustion. J Immunother Cancer 2024; 12:e008898. [PMID: 39562007 PMCID: PMC11580249 DOI: 10.1136/jitc-2024-008898] [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: 10/04/2024] [Indexed: 11/21/2024] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, highly resistant to standard chemotherapy and immunotherapy. Regulatory T cells (Tregs) expressing tumor necrosis factor α receptor 2 (TNFR2) contribute to immunosuppression in PDAC. Treg infiltration correlates with poor survival and tumor progression in patients with PDAC. We hypothesized that TNFR2 inhibition using a blocking monoclonal antibody (mAb) could shift the Treg-effector T cell balance in PDAC, thus enhancing antitumoral responses. METHOD To support this hypothesis, we first described TNFR2 expression in a cohort of 24 patients with PDAC from publicly available single-cell analysis data. In orthotopic and immunocompetent mouse models of PDAC, we also described the immune environment of PDAC after immune cell sorting and single-cell analysis. The modifications of the immune environment before and after anti-TNFR2 mAb treatment were evaluated as well as the effect on tumor progression. RESULTS Patients with PDAC exhibited elevated TNFR2 expression in Treg, myeloid cells and endothelial cells and lower level in tumor cells. By flow cytometry and single-cell RNA-seq analysis, we identified two Treg populations in orthotopic mouse models: Resting and activated Tregs. The anti-TNFR2 mAb selectively targeted activated tumor-infiltrating Tregs, reducing T cell exhaustion markers in CD8+ T cells. However, anti-TNFR2 treatment alone had limited efficacy in activating CD8+ T cells and only slightly reduced the tumor growth. The combination of the anti-TNFR2 mAb with agonistic anti-CD40 mAb promoted stronger T cell activation, tumor growth inhibition, and improved survival and immunological memory in PDAC-bearing mice. CONCLUSION Our data suggest that combining a CD40 agonist with a TNFR2 antagonist represents a promising therapeutic strategy for patients with PDAC.
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Affiliation(s)
- Anais Debesset
- INSERM, IMRB U955, Université Paris-Est Créteil Val de Marne, Créteil, France
| | - Caroline Pilon
- INSERM, IMRB U955, Université Paris-Est Créteil Val de Marne, Créteil, France
- CIC Biotherapy, Fédération hospitalo-Universitaire TRUE, AP-HP, GH Henri Mondor, Créteil, France
| | - Sylvain Meunier
- INSERM, IMRB U955, Université Paris-Est Créteil Val de Marne, Créteil, France
| | | | - Wilfrid Richer
- INSERM U932, Institute Curie Research Center, PSL Research University, Paris, France
- Department of Translational Research, Institut Curie Research center, PSL Research University, Paris, France
| | - Allan Thiolat
- INSERM, IMRB U955, Université Paris-Est Créteil Val de Marne, Créteil, France
| | - Claire Houppe
- INSERM, IMRB U955, Université Paris-Est Créteil Val de Marne, Créteil, France
| | - Matteo Ponzo
- INSERM, IMRB U955, Université Paris-Est Créteil Val de Marne, Créteil, France
| | - Jeanne Magnan
- INSERM, IMRB U955, Université Paris-Est Créteil Val de Marne, Créteil, France
| | - Jonathan Caron
- INSERM, IMRB U955, Université Paris-Est Créteil Val de Marne, Créteil, France
| | - Pamela Caudana
- INSERM U932, Institute Curie Research Center, PSL Research University, Paris, France
- Department of Translational Research, Institut Curie Research center, PSL Research University, Paris, France
| | - Jimena Tosello Boari
- INSERM U932, Institute Curie Research Center, PSL Research University, Paris, France
- Department of Translational Research, Institut Curie Research center, PSL Research University, Paris, France
| | - Sylvain Baulande
- Institut Curie Research Center, ICGex Next-Generation Sequencing Platform, Single Cell Initiative, PSL Research University, Paris, France
| | - Nhu Han To
- INSERM, IMRB U955, Université Paris-Est Créteil Val de Marne, Créteil, France
- Department of Radiation Oncology, Henri Mondor Breast Center, AP-HP, GH Henri Mondor, Paris, France
| | - Benoit Laurent Salomon
- Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM UMR1291, CNRS UMR5051, University Toulouse III, Toulouse, France
| | - Eliane Piaggio
- INSERM U932, Institute Curie Research Center, PSL Research University, Paris, France
- Department of Translational Research, Institut Curie Research center, PSL Research University, Paris, France
| | - Ilaria Cascone
- INSERM, IMRB U955, Université Paris-Est Créteil Val de Marne, Créteil, France
| | - José Laurent Cohen
- INSERM, IMRB U955, Université Paris-Est Créteil Val de Marne, Créteil, France
- CIC Biotherapy, Fédération hospitalo-Universitaire TRUE, AP-HP, GH Henri Mondor, Créteil, France
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Wu Y, Sun X, Kang K, Yang Y, Li H, Zhao A, Niu T. Hemophagocytic lymphohistiocytosis: current treatment advances, emerging targeted therapy and underlying mechanisms. J Hematol Oncol 2024; 17:106. [PMID: 39511607 PMCID: PMC11542428 DOI: 10.1186/s13045-024-01621-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Accepted: 10/14/2024] [Indexed: 11/15/2024] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a rapidly progressing, life-threatening syndrome characterized by excessive immune activation, often presenting as a complex cytokine storm. This hyperactive immune response can lead to multi-organ failure and systemic damage, resulting in an extremely short survival period if left untreated. Over the past decades, although HLH has garnered increasing attention from researchers, there have been few advancements in its treatment. The cytokine storm plays a crucial role in the treatment of HLH. Investigating the detailed mechanisms behind cytokine storms offers insights into targeted therapeutic approaches, potentially aiding in early intervention and improving the clinical outcome of HLH patients. To date, there is only one targeted therapy, emapalumab targeting interferon-γ, that has gained approval for primary HLH. This review aims to summarize the current treatment advances, emerging targeted therapeutics and underlying mechanisms of HLH, highlighting its newly discovered targets potentially involved in cytokine storms, which are expected to drive the development of novel treatments and offer fresh perspectives for future studies. Besides, multi-targeted combination therapy may be essential for disease control, but further trials are required to determine the optimal treatment mode for HLH.
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Affiliation(s)
- Yijun Wu
- Department of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- National Facility for Translational Medicine (Sichuan), West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xu Sun
- Department of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- National Facility for Translational Medicine (Sichuan), West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Kai Kang
- Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- National Facility for Translational Medicine (Sichuan), West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yuqi Yang
- West China School of Medicine, Sichuan University, Chengdu, Sichuan, China
| | - He Li
- Department of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- National Facility for Translational Medicine (Sichuan), West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Ailin Zhao
- Department of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
- State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
- National Facility for Translational Medicine (Sichuan), West China Hospital, Sichuan University, Chengdu, Sichuan, China.
| | - Ting Niu
- Department of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
- State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
- National Facility for Translational Medicine (Sichuan), West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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Li L, Ye R, Li Y, Pan H, Han S, Lu Y. Targeting TNFR2 for cancer immunotherapy: recent advances and future directions. J Transl Med 2024; 22:812. [PMID: 39223671 PMCID: PMC11367783 DOI: 10.1186/s12967-024-05620-x] [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: 04/17/2024] [Accepted: 08/18/2024] [Indexed: 09/04/2024] Open
Abstract
Cancer is the leading cause of death worldwide, accounting for nearly 10 million deaths every year. Immune checkpoint blockade approaches have changed the therapeutic landscape for many tumor types. However, current immune checkpoint inhibitors PD-1 or CTLA-4 are far from satisfactory, due to high immune-related adverse event incident (up to 60%) and the inefficiency in cases of "cold" tumor microenvironment. TNFR2, a novel hopeful tumor immune target, was initially proposed in 2017. It not only promotes tumor cell proliferation, but also correlates with the suppressive function of Treg cells, implicating in the development of an immunosuppressive tumor microenvironment. In preclinical studies, TNFR2 antibody therapy has demonstrated efficacy alone or a potential synergistic effect when combined with classical PD-1/ CTLA-4 antibodies. The focus of this review is on the characteristics, functions, and recent advancements in TNFR2 therapy, providing a new direction for the next generation of anti-tumor alternative therapy.
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Affiliation(s)
- Linxue Li
- Shanghai Baoshan Luodian Hospital, School of Medicine, Shanghai University, Shanghai, 201908, China
| | - Ruiwei Ye
- Shanghai Baoshan Luodian Hospital, School of Medicine, Shanghai University, Shanghai, 201908, China
| | - Yingying Li
- Shanghai Baoshan Luodian Hospital, School of Medicine, Shanghai University, Shanghai, 201908, China
| | - Hanyu Pan
- Shanghai Baoshan Luodian Hospital, School of Medicine, Shanghai University, Shanghai, 201908, China
| | - Sheng Han
- Shanghai Baoshan Luodian Hospital, School of Medicine, Shanghai University, Shanghai, 201908, China.
| | - Yiming Lu
- Shanghai Baoshan Luodian Hospital, School of Medicine, Shanghai University, Shanghai, 201908, China.
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Huang S, Liu D, Han L, Deng J, Wang Z, Jiang J, Zeng L. Decoding the potential role of regulatory T cells in sepsis-induced immunosuppression. Eur J Immunol 2024; 54:e2350730. [PMID: 38430202 DOI: 10.1002/eji.202350730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 02/14/2024] [Accepted: 02/16/2024] [Indexed: 03/03/2024]
Abstract
Sepsis, a multiorgan dysfunction with high incidence and mortality, is caused by an imbalanced host-to-infection immune response. Organ-support therapy improves the early survival rate of sepsis patients. In the long term, those who survive the "cytokine storm" and its secondary damage usually show higher susceptibility to secondary infections and sepsis-induced immunosuppression, in which regulatory T cells (Tregs) are evidenced to play an essential role. However, the potential role and mechanism of Tregs in sepsis-induced immunosuppression remains elusive. In this review, we elucidate the role of different functional subpopulations of Tregs during sepsis and then review the mechanism of sepsis-induced immunosuppression from the aspects of regulatory characteristics, epigenetic modification, and immunometabolism of Tregs. Thoroughly understanding how Tregs impact the immune system during sepsis may shed light on preclinical research and help improve the translational value of sepsis immunotherapy.
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Affiliation(s)
- Siyuan Huang
- Department of Trauma Medical Center, Daping Hospital, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
| | - Di Liu
- Department of Trauma Medical Center, Daping Hospital, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
| | - Lei Han
- Department of Trauma Medical Center, Daping Hospital, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
| | - Jin Deng
- Department of Emergency, the Affiliated Hospital of Guizhou Medical University, Guizhou Medical University, Guiyang, China
| | - Zhen Wang
- Department of Trauma Medical Center, Daping Hospital, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
| | - Jianxin Jiang
- Department of Trauma Medical Center, Daping Hospital, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
| | - Ling Zeng
- Department of Trauma Medical Center, Daping Hospital, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
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Qian X, Jin M, Bei Y, Zhou C, Fang S, Liu K. SLC20A1 is a prospective prognostic and therapy response predictive biomarker in head and neck squamous cell carcinoma. Aging (Albany NY) 2024; 16:4423-4444. [PMID: 38412319 PMCID: PMC10968711 DOI: 10.18632/aging.205597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 01/11/2024] [Indexed: 02/29/2024]
Abstract
BACKGROUND SLC20A1, a prominent biomarker in several cancers, has been understudied in its predictive role in head and neck squamous cell carcinoma (HNSCC). METHODS The Cancer Genome Atlas (TCGA) database was used to analyze HNSCC prognosis, SLC20A1 overexpression, and clinical characteristics. Quantitative real-time PCR and Western blot analysis confirmed SLC20A1 expression in HNSCC tissues. Cellular behaviors such as invasion, migration and proliferation were assessed using Transwell, wound healing and colony formation assays. Immune system data were obtained from the Tumor Immune Estimation Resource (TIMER) and CIBERSORT databases. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) were used to explore biological parameters and pathways associated with SLC20A1 overexpression in HNSCC. RESULTS In 499 HNSCC samples, SLC20A1 mRNA and protein expression were significantly higher than in 44 normal counterparts, confirmed by 24 paired samples. Patients were categorized based on SLC20A1 levels, survival status and overall survival. High SLC20A1 expression correlated with advanced T stage, increased risk scores and decreased survival. Stage, age and SLC20A1 expression emerged as independent predictive factors for HNSCC in univariate and multivariate analyses. SLC20A1 overexpression, which is associated with poor prognosis, may influence cell proliferation, migration, invasion, chemotherapy response, and the immune milieu. CONCLUSIONS SLC20A1 overexpression in HNSCC, characterized by increased cellular invasion, migration and proliferation, is a potential prognostic biomarker and therapeutic response indicator.
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Affiliation(s)
- Xiajing Qian
- Department of Radiation Oncology, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
| | - Ming Jin
- Department of Radiation Oncology, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
| | - Yanping Bei
- Department of Radiation Oncology, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
| | - Chongchang Zhou
- Department of Otorhinolaryngology Head and Neck Surgery, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
| | - Shuai Fang
- Department of Thoracic Surgery, The Affiliated Hospital of Medical School of Ningbo University, Ningbo, Zhejiang, China
| | - Kaitai Liu
- Department of Radiation Oncology, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
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Jing Q, Wan Q, Nie Y, Luo J, Zhang X, Zhu L, Gui H, Li L, Wang C, Chen S, Wang M, Yuan H, Lv H, Pan R, Jing Q, Nie Y. Ansofaxine hydrochloride inhibits tumor growth and enhances Anti-TNFR2 in murine colon cancer model. Front Pharmacol 2023; 14:1286061. [PMID: 38161697 PMCID: PMC10755865 DOI: 10.3389/fphar.2023.1286061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Accepted: 12/01/2023] [Indexed: 01/03/2024] Open
Abstract
Introduction: As psychoneuroimmunology flourishes, there is compelling evidence that depression suppresses the anti-tumor immune response, promotes the progression of cancer, and inhibits the effectiveness of cancer immunotherapy. Recent studies have reported that antidepressants can not only alleviate the depressant condition of cancer patients, but also strengthen the anti-tumor immunity, thus suppressing tumors. Tumor necrosis factor receptor 2 (TNFR2) antagonistic antibodies (Anti-TNFR2) targeting tumor-infiltrating regulatory T cells (Tregs) has achieved great results in preclinical studies, and with a favorable toxicity profile than existing immunotherapies, and is expected to become a new generation of more effective treatment strategies. Understanding the effects of combination therapy with antidepressants and Anti-TNFR2 may help design new strategies for cancer immunotherapy. Methods: We treated CT26, HCT116, MCA38 and SW620 colon cancer cells with fluoxetine (0-50 µM), ansofaxine hydrochloride (0-50 µM) and amitifadine hydrochloride (0-150 µM) to examine their effects on cell proliferation and apoptosis. We explored the antitumor effects of ansofaxine hydrochloride in combination with or without Anti-TNFR in subcutaneously transplanted CT26 cells in tumor-bearing mouse model. Antitumor effects were evaluated by tumor volume. NK cell, M1 macrophage cell, CD4+ T cell, CD8+ T cell, exhausted CD8+ T and regulatory T cell (Tregs) subtypes were measured by flow cytometry. 5-hydroxytryptamine, dopamine and norepinephrine levels were measured by ELISA. Results: Oral antidepression, ansofaxine hydrochloride, enhanced peripheral dopamine levels, promoted CD8+T cell proliferation, promoted intratumoral infiltration of M1 and NK cells, decreased the proportion of tumor-infiltrating exhausted CD8+T cells, and strengthened anti-tumor immunity, thereby inhibiting colon cancer growth. In combination therapy, oral administration of ansofaxine hydrochloride enhanced the efficacy of Anti-TNFR2, and produced long-term tumor control in with syngeneic colorectal tumor-bearing mice, which was attributable to the reduction in tumor-infiltrating Treg quantity and the recovery of CD8+ T cells function. Discussion: In summary, our data reveal the role of ansofaxine hydrochloride in modulating the anti-tumor immunity. Our results support that exhausted CD8+T is an important potential mechanism by which ansofaxine hydrochloride activates anti-tumor immunity and enhances anti-tumor effects of anti-TNFR2.
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Affiliation(s)
- Qianyu Jing
- School of Basic Medical Sciences, Zunyi Medical University, Zunyi, China
| | - Quan Wan
- School of Basic Medical Sciences, Zunyi Medical University, Zunyi, China
| | - Yujie Nie
- NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People’s Hospital, Guiyang, China
| | - Junqian Luo
- The First People’s Hospital of Jinzhong, Jinzhong, China
| | - Xiangyan Zhang
- NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People’s Hospital, Guiyang, China
| | - Lan Zhu
- School of Medicine, Guizhou University, Guiyang, China
| | - Huan Gui
- School of Medicine, Guizhou University, Guiyang, China
| | - Linzhao Li
- School of Medicine, Guizhou University, Guiyang, China
| | - Chenglv Wang
- School of Medicine, Guizhou University, Guiyang, China
| | | | - Mengjiao Wang
- School of Medicine, Guizhou University, Guiyang, China
| | - Haohua Yuan
- School of Medicine, Guizhou University, Guiyang, China
| | - Hang Lv
- School of Medicine, Guizhou University, Guiyang, China
| | | | | | - Yingjie Nie
- School of Basic Medical Sciences, Zunyi Medical University, Zunyi, China
- NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People’s Hospital, Guiyang, China
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9
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Mei X, Ouyang H, Zhang H, Jia W, Lu B, Zhang J, Ji L. Scutellarin suppresses the metastasis of triple-negative breast cancer via targeting TNFα/TNFR2-RUNX1-triggered G-CSF expression in endothelial cells. Biochem Pharmacol 2023; 217:115808. [PMID: 37716622 DOI: 10.1016/j.bcp.2023.115808] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 09/13/2023] [Accepted: 09/13/2023] [Indexed: 09/18/2023]
Abstract
Triple-negative breast cancer (TNBC) is heterogeneous and aggressive, with high vascularity and frequent metastasis. We have already found natural flavonoid scutellarin (SC) suppressed spontaneous TNBC metastasis via normalizing tumor vasculature in vivo. In this study, supernatant from tumor necrosis factorα (TNFα)-treated human mammary microvascular endothelial cell (HMMEC) promoted cell migration and pseudopod formation in TNBC cells, but these phenomena were disappeared in SC-co-treated HMMEC. TNFα enhanced the expression of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in both HMMEC and human umbilical vein endothelial cell (HUVEC). G-CSF promoted TNBC migration and invasion in vitro, while G-CSF neutralization antibody and SC both inhibited TNBC metastasis in Balb/c mice. SC had no inhibition on the G-CSF-induced TNBC cell migration, but reduced G-CSF content in TNBC tumor tissues and TNFα-stimulated endothelial cells (ECs). SC restricted the nuclear translocation of runt-related transcription factor 1 (RUNX1) in TNBC tumor vessels and TNFα-treated ECs. RUNX1 was found to directly bind to the promoter of G-CSF in TNBC tumor vessels and regulated G-CSF expression. TNF receptor 2 (TNFR2) was crucial for regulating the TNFα-induced RUNX1 activation and G-CSF expression. Notably, SC hindered the interaction between TNFα and TNFR2 via binding to TNFR2. This work demonstrated that SC reduced TNBC metastasis by targeting TNFα/TNFR2-initiated RUNX1 activation and subsequent G-CSF production in TNBC-associated ECs.
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Affiliation(s)
- Xiyu Mei
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Key Laboratory of Research and Development of Chinese Medicine of Zhejiang Province, Key Laboratory of Pharmacodynamic Material Basis Research in Chinese Medicine of Zhejiang Province, Institute of Basic Medicine, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou 310007, China
| | - Hao Ouyang
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Hong Zhang
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Wangya Jia
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Bin Lu
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jingnan Zhang
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Lili Ji
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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10
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Chen Y, Jiang M, Chen X. Therapeutic potential of TNFR2 agonists: a mechanistic perspective. Front Immunol 2023; 14:1209188. [PMID: 37662935 PMCID: PMC10469862 DOI: 10.3389/fimmu.2023.1209188] [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: 04/20/2023] [Accepted: 07/31/2023] [Indexed: 09/05/2023] Open
Abstract
TNFR2 agonists have been investigated as potential therapies for inflammatory diseases due to their ability to activate and expand immunosuppressive CD4+Foxp3+ Treg cells and myeloid-derived suppressor cells (MDSCs). Despite TNFR2 being predominantly expressed in Treg cells at high levels, activated effector T cells also exhibit a certain degree of TNFR2 expression. Consequently, the role of TNFR2 signaling in coordinating immune or inflammatory responses under different pathological conditions is complex. In this review article, we analyze possible factors that may determine the therapeutic outcomes of TNFR2 agonism, including the levels of TNFR2 expression on different cell types, the biological properties of TNFR2 agonists, and disease status. Based on recent progress in the understanding of TNFR2 biology and the study of TNFR2 agonistic agents, we discuss the future direction of developing TNFR2 agonists as a therapeutic agents.
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Affiliation(s)
- Yibo Chen
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, Macau SAR, China
| | - Mengmeng Jiang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, Macau SAR, China
| | - Xin Chen
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, Macau SAR, China
- Ministry of Education (MoE) Frontiers Science Center for Precision Oncology, University of Macau, Macau, Macau SAR, China
- Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, Macau, Macau SAR, China
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Macau, Macau SAR, China
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11
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Zhao X, Lu Y, Cui L. Neutrophil-sourced TNF in cancer: deciphering an intricate orchestrator of immunosuppressive communication in the tumor microenvironment. Signal Transduct Target Ther 2023; 8:272. [PMID: 37455286 DOI: 10.1038/s41392-023-01530-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 05/24/2023] [Accepted: 06/04/2023] [Indexed: 07/18/2023] Open
Affiliation(s)
- Xinyuan Zhao
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, Guangdong, China
| | - Ye Lu
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, Guangdong, China
| | - Li Cui
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, Guangdong, China.
- Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, Los Angeles, 90095, CA, USA.
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12
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Dadas O, Ertay A, Cragg MS. Delivering co-stimulatory tumor necrosis factor receptor agonism for cancer immunotherapy: past, current and future perspectives. Front Immunol 2023; 14:1147467. [PMID: 37180119 PMCID: PMC10167284 DOI: 10.3389/fimmu.2023.1147467] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 03/27/2023] [Indexed: 05/15/2023] Open
Abstract
The tumor necrosis factor superfamily (TNFSF) and their receptors (TNFRSF) are important regulators of the immune system, mediating proliferation, survival, differentiation, and function of immune cells. As a result, their targeting for immunotherapy is attractive, although to date, under-exploited. In this review we discuss the importance of co-stimulatory members of the TNFRSF in optimal immune response generation, the rationale behind targeting these receptors for immunotherapy, the success of targeting them in pre-clinical studies and the challenges in translating this success into the clinic. The efficacy and limitations of the currently available agents are discussed alongside the development of next generation immunostimulatory agents designed to overcome current issues, and capitalize on this receptor class to deliver potent, durable and safe drugs for patients.
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Affiliation(s)
- Osman Dadas
- Antibody and Vaccine Group, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Ayse Ertay
- School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Mark S. Cragg
- Antibody and Vaccine Group, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
- Institute for Life Sciences, University of Southampton, Southampton, United Kingdom
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13
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Zhu L, Zhang X, Chen X, Yang D, Nie Y, Pan R, Li L, Wang C, Gui H, Chen S, Jing Q, Wang M, Nie Y. Anti-TNFR2 enhanced the antitumor activity of a new HMGN1/3M-052 stimulated dendritic cell vaccine in a mouse model of colon cancer. Biochem Biophys Res Commun 2023; 653:106-114. [PMID: 36868074 DOI: 10.1016/j.bbrc.2023.02.039] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 02/15/2023] [Indexed: 02/18/2023]
Abstract
Immunotherapy is the new approach for cancer treatment that can be achieved through several strategies, one of which is dendritic cells (DCs) vaccine therapy. However, traditional DC vaccination lacks accurate targeting, so DC vaccine preparation needs to be optimized. Immunosuppressive CD4+Foxp3+ regulatory T cells (Tregs) in the tumor microenvironment can promote tumor immune escape. Therefore, targeting Tregs has become a strategy for tumor immunotherapy. In this study, we found that HMGN1 (N1, a dendritic cell-activating TLR4 agonist) and 3M-052 (a newly synthesized TLR7/8 agonist) synergistically stimulate DCs maturation and increase the production of proinflammatory cytokines TNFα and IL-12. In a colon cancer mice model, vaccination with N1 and 3M-052 stimulated and tumor antigen-loaded DCs combined with anti-TNFR2 inhibited tumor growth in mice, and the antitumor effect was mainly achieved through stimulation of cytotoxic CD8 T cell activation and depletion of Tregs. Overall, the combinating of DC activation by N1 and 3M-052 with inhibition of Tregs by antagonizing TNFR2 as a therapeutic strategy may represent a more effective strategy for cancer treatment.
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Affiliation(s)
- Lan Zhu
- School of Medicine, Guizhou University, Guiyang, 550025, China.
| | - Xiangyan Zhang
- NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People's Hospital, Guiyang, 550002, China.
| | - Xin Chen
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR, 999078, China.
| | - De Yang
- Laboratory of Cancer Immunometabolism, Center for Cancer Research, National Cancer Institute at Frederick, NIH, Frederick, MD, USA.
| | - Yujie Nie
- NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People's Hospital, Guiyang, 550002, China.
| | - Runsang Pan
- Department of Pathophysiology, School of Basic Medicine, Guizhou Medical University, Guiyang, 550025, China.
| | - Linzhao Li
- School of Medicine, Guizhou University, Guiyang, 550025, China.
| | - Chenglv Wang
- School of Medicine, Guizhou University, Guiyang, 550025, China.
| | - Huan Gui
- School of Medicine, Guizhou University, Guiyang, 550025, China.
| | - Shuanghui Chen
- School of Medicine, Guizhou University, Guiyang, 550025, China.
| | - Qianyu Jing
- School of Preclinical Medicine of Zunyi Medical University, Zunyi, 563000, China.
| | - Mengjiao Wang
- School of Medicine, Guizhou University, Guiyang, 550025, China.
| | - Yingjie Nie
- NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People's Hospital, Guiyang, 550002, China; School of Medicine, Guizhou University, Guiyang, 550025, China.
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14
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TNFR2 antagonistic antibody induces the death of tumor infiltrating CD4 +Foxp3 + regulatory T cells. Cell Oncol (Dordr) 2023; 46:167-177. [PMID: 36369606 DOI: 10.1007/s13402-022-00742-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/26/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND TNFR2 expression is a characteristic of highly potent immunosuppressive tumor infiltrating CD4+Foxp3+ regulatory T cells (Tregs). There is compelling evidence that TNF through TNFR2 preferentially stimulates the activation and expansion of Tregs. We and others, therefore, proposed that targeting TNFR2 may provide a novel strategy in cancer immunotherapy. Several studies have shown the effect of TNFR2 antagonistic antibodies in different tumor models. However, the exact action of the TNFR2 antibody on Tregs remained understood. METHOD TY101, an anti-murine TNFR2 antibody, was used to examine the effect of TNFR2 blockade on Treg proliferation and viability in vitro. The role of TNFR2 on Treg viability was further validated by TNFR2 knockout mice and in the TY101 antagonistic antibody-treated mouse tumor model. RESULTS In this study, we found that an anti-mouse TNFR2 antibody TY101 could inhibit TNF-induced proliferative expansion of Tregs, indicative of an antagonistic property. To examine the effect of TY101 antagonistic antibody on Treg viability, we treated unfractionated lymph node (L.N.) cells with Dexamethasone (Dex) which was known to induce T cell death. The result showed that TY101 antagonistic antibody treatment further promoted Treg death in the presence of Dex. This led us to find that TNFR2 expression was crucial for the survival of Tregs. In the mouse EG7 lymphoma model, treatment with TY101 antagonistic antibody potently inhibited tumor growth, resulting in complete regression of the tumor in 60% of mice. The treatment with TY101 antagonistic antibody elicited potent antitumor immune responses in this model, accompanied by enhanced death of Tregs. CONCLUSION This study, therefore, provides clear experimental evidence that TNFR2 antagonistic antibody, TY101, can promote the death of Tregs, and this effect may be attributable to the antitumor effect of TNFR2 antagonistic antibody.
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15
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Quazi S. TNFR2 antagonist and agonist: a potential therapeutics in cancer immunotherapy. Med Oncol 2022; 39:215. [PMID: 36175687 DOI: 10.1007/s12032-022-01772-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Accepted: 06/15/2022] [Indexed: 11/26/2022]
Abstract
Tumour necrosis factor receptor 2 or TNFR2 is considered an appealing target protein due to its limited frequency to TREGs, which are highly immunosuppressive and present on human malignancies. Numerous studies have revealed that TNFR2 is primarily found on MDSCs (myeloid-derived suppressor cells) and CD + Foxp3 + regulatory T cells (TREGs). Therefore, it has great importance in the proliferation and functional activity of TREGs and MDSCs. TNFR2 suppression must be downregulated or upregulated as required to treat malignancies and diseases like autoimmune disorders. Therefore, at the molecular level, advances in the comprehension of TNFR2's complex structure and its binding to TNF have opened the door to structure-guided drug development. Two critical obstacles to cancer treatment are the dearth of TREG-specific inhibitors and the lack of widely applicable ways to target tumours via frequently expressed surface oncogenes directly. Many researchers have discovered potential antagonists and agonists of TNFR2, which were successful in inhibiting TREGs proliferation, reducing soluble TNFR2 secretion from normal cells, and expanding T effector cells. The data represented in the following review article elucidates the clinically administrated TNFR2 antagonist and agonist in treating cancers.
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Affiliation(s)
- Sameer Quazi
- GenLab Biosolutions Private Limited, Bangalore, 560043, Karnataka, India.
- Department of Biomedical Sciences, School of Life Sciences, Anglia Ruskin University, Cambridge, UK.
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.
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16
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Chen S, Li R, Chen Y, Chou CK, Zhang Z, Yang Y, Liao P, Wang Q, Chen X. Scutellarin enhances anti-tumor immune responses by reducing TNFR2-expressing CD4 +Foxp3 + regulatory T cells. Biomed Pharmacother 2022; 151:113187. [PMID: 35676787 DOI: 10.1016/j.biopha.2022.113187] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 05/11/2022] [Accepted: 05/22/2022] [Indexed: 11/26/2022] Open
Abstract
One characteristic of tumor-associated CD4+Foxp3+ regulatory T cells (Tregs) is the high expression of tumor necrosis factor receptor type II (TNFR2), a receptor that mediates the decisive effect of tumor necrosis factor (TNF) in the activation and expansion of Tregs. There is increasing evidence that inhibition of TNFR2 can enhance anti-tumor immune responses. Therefore, we screened Chinese herbal extracts for their capacity to block TNF-TNFR2 interaction. The results showed that the treatment with a Chinese herb extract could inhibit TNFR2-induced biological responses in vitro, including the proliferation of TNFR2+ Tregs. Our subsequent study led to the identification of flavonoid compound scutellarin was responsible for the activity. Our results showed that scutellarin is able to disrupt the interaction of TNF-TNFR2 and inhibited the phosphorylation of p38 MAPK, a down-stream signaling component of TNFR2. Importantly, in vivo scutellarin treatment markedly enhanced the efficacy of tumor immunotherapy with CpG oligodeoxynucleotide in mouse CT26 colon cancer model. This effect of scutellarin was associated with the reduction of the number of tumor-infiltrating TNFR2-expressing Tregs and increased tumor infiltration of interferon-γ-producing CD8+ T cells. Our result also suggests that scutellarin or its analogs may be used as an adjuvant to enhance the anti-tumor effect of immunotherapeutic agent by eliminating TNFR2+ Treg activity.
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Affiliation(s)
- Shaokui Chen
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, 999078, Macao Special Administrative Region of China, China
| | - Ruixin Li
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, 999078, Macao Special Administrative Region of China, China
| | - Yibo Chen
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, 999078, Macao Special Administrative Region of China, China
| | - Chon-Kit Chou
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, 999078, Macao Special Administrative Region of China, China
| | - Zhexuan Zhang
- College of Science, Hunan University of Technology and Business, Changsha 410205, China
| | - Yang Yang
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, 999078, Macao Special Administrative Region of China, China
| | - Ping Liao
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, 999078, Macao Special Administrative Region of China, China
| | - Qingqing Wang
- Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Xin Chen
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, 999078, Macao Special Administrative Region of China, China; Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, 999078, Macao Special Administrative Region of China, China; MoE Frontiers Science Center for Precision Oncology, University of Macau, 999078, Macao Special Administrative Region of China, China; Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, University of Macau, 999078, Macao Special Administrative Region of China, China.
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17
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Takahashi H, Yoshimatsu G, Faustman DL. The Roles of TNFR2 Signaling in Cancer Cells and the Tumor Microenvironment and the Potency of TNFR2 Targeted Therapy. Cells 2022; 11:1952. [PMID: 35741080 DOI: 10.3390/cells11121952pubmedhttps:/www.ncbi.nlm.nih.gov/pubmed/35741080pubmed] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 06/08/2022] [Accepted: 06/14/2022] [Indexed: 08/02/2024] Open
Abstract
The appreciation that cancer growth is promoted by a dynamic tumor microenvironment (TME) has spawned novel approaches to cancer treatment. New therapies include agents that activate quiescent T effector cells and agents that interfere with abnormal neovascularity. Although promising, many experimental therapies targeted at the TME have systemic toxicity. Another approach is to target the TME with greater specificity by taking aim at the tumor necrosis factor receptor 2 (TNFR2) signaling pathway. TNFR2 is an attractive molecular target because it is rarely expressed in normal tissues (thus, has low potential for systemic toxicity) and because it is overexpressed on many types of cancer cells as well as on associated TME components, such as T regulatory cells (Tregs), tumor-associated macrophages, and other cells that facilitate tumor progression and spread. Novel therapies that block TNFR2 signaling show promise in cell culture studies, animal models, and human studies. Novel antibodies have been developed that expressly kill only rapidly proliferating cells expressing newly synthesized TNFR2 protein. This review traces the origins of our understanding of TNFR2's multifaceted roles in the TME and discusses the therapeutic potential of agents designed to block TNFR2 as the cornerstone of a TME-specific strategy.
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Affiliation(s)
- Hiroyuki Takahashi
- Department of Gastroenterological Surgery, Fukuoka University Hospital, Fukuoka 814-0180, Japan
- Immunobiology Department, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
| | - Gumpei Yoshimatsu
- Department of Gastroenterological Surgery, Fukuoka University Hospital, Fukuoka 814-0180, Japan
| | - Denise Louise Faustman
- Immunobiology Department, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
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18
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Takahashi H, Yoshimatsu G, Faustman DL. The Roles of TNFR2 Signaling in Cancer Cells and the Tumor Microenvironment and the Potency of TNFR2 Targeted Therapy. Cells 2022; 11:cells11121952. [PMID: 35741080 PMCID: PMC9222015 DOI: 10.3390/cells11121952] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 06/08/2022] [Accepted: 06/14/2022] [Indexed: 11/16/2022] Open
Abstract
The appreciation that cancer growth is promoted by a dynamic tumor microenvironment (TME) has spawned novel approaches to cancer treatment. New therapies include agents that activate quiescent T effector cells and agents that interfere with abnormal neovascularity. Although promising, many experimental therapies targeted at the TME have systemic toxicity. Another approach is to target the TME with greater specificity by taking aim at the tumor necrosis factor receptor 2 (TNFR2) signaling pathway. TNFR2 is an attractive molecular target because it is rarely expressed in normal tissues (thus, has low potential for systemic toxicity) and because it is overexpressed on many types of cancer cells as well as on associated TME components, such as T regulatory cells (Tregs), tumor-associated macrophages, and other cells that facilitate tumor progression and spread. Novel therapies that block TNFR2 signaling show promise in cell culture studies, animal models, and human studies. Novel antibodies have been developed that expressly kill only rapidly proliferating cells expressing newly synthesized TNFR2 protein. This review traces the origins of our understanding of TNFR2’s multifaceted roles in the TME and discusses the therapeutic potential of agents designed to block TNFR2 as the cornerstone of a TME-specific strategy.
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Affiliation(s)
- Hiroyuki Takahashi
- Department of Gastroenterological Surgery, Fukuoka University Hospital, Fukuoka 814-0180, Japan; (H.T.); (G.Y.)
- Immunobiology Department, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
| | - Gumpei Yoshimatsu
- Department of Gastroenterological Surgery, Fukuoka University Hospital, Fukuoka 814-0180, Japan; (H.T.); (G.Y.)
| | - Denise Louise Faustman
- Immunobiology Department, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
- Correspondence: ; Tel.: +1-617-726-4084; Fax: +1-617-726-4095
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19
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Ben-Baruch A. Tumor Necrosis Factor α: Taking a Personalized Road in Cancer Therapy. Front Immunol 2022; 13:903679. [PMID: 35663982 PMCID: PMC9157545 DOI: 10.3389/fimmu.2022.903679] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 04/25/2022] [Indexed: 11/29/2022] Open
Affiliation(s)
- Adit Ben-Baruch
- The Shmunis School of Biomedicine and Cancer Research, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
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20
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Medler J, Kucka K, Wajant H. Tumor Necrosis Factor Receptor 2 (TNFR2): An Emerging Target in Cancer Therapy. Cancers (Basel) 2022; 14:cancers14112603. [PMID: 35681583 PMCID: PMC9179537 DOI: 10.3390/cancers14112603] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 05/19/2022] [Accepted: 05/22/2022] [Indexed: 12/12/2022] Open
Abstract
Despite the great success of TNF blockers in the treatment of autoimmune diseases and the identification of TNF as a factor that influences the development of tumors in many ways, the role of TNFR2 in tumor biology and its potential suitability as a therapeutic target in cancer therapy have long been underestimated. This has been fundamentally changed with the identification of TNFR2 as a regulatory T-cell (Treg)-stimulating factor and the general clinical breakthrough of immunotherapeutic approaches. However, considering TNFR2 as a sole immunosuppressive factor in the tumor microenvironment does not go far enough. TNFR2 can also co-stimulate CD8+ T-cells, sensitize some immune and tumor cells to the cytotoxic effects of TNFR1 and/or acts as an oncogene. In view of the wide range of cancer-associated TNFR2 activities, it is not surprising that both antagonists and agonists of TNFR2 are considered for tumor therapy and have indeed shown overwhelming anti-tumor activity in preclinical studies. Based on a brief summary of TNFR2 signaling and the immunoregulatory functions of TNFR2, we discuss here the main preclinical findings and insights gained with TNFR2 agonists and antagonists. In particular, we address the question of which TNFR2-associated molecular and cellular mechanisms underlie the observed anti-tumoral activities of TNFR2 agonists and antagonists.
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21
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Signaling pathway(s) of TNFR2 required for the immunoregulatory effect of CD4 +Foxp3 + regulatory T cells. Int Immunopharmacol 2022; 108:108823. [PMID: 35623290 DOI: 10.1016/j.intimp.2022.108823] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 04/26/2022] [Accepted: 04/29/2022] [Indexed: 11/23/2022]
Abstract
CD4+Foxp3+ regulatory T cells (Tregs), a subpopulation of CD4+ T cells, are engaged in maintaining the periphery tolerance and preventing autoimmunity. Recent studies showed that tumor necrosis factor receptor 2 (TNFR2) is preferentially expressed by Tregs and the expression of this receptor identifies the maximally suppressive Tregs. That is, TNFR2 is a liable phenotypic and functional surface marker of Tregs. Moreover, TNF activates and expands Tregs through TNFR2. However, it is very interesting which signaling pathway(s) of TNFR2 is required for the inhibitory effect of Tregs. Compelling evidence shows three TNFR2 signaling pathways in Tregs, including NF-κB, MAPK and PI3K-Akt pathways. Here, we summarize and discuss the latest progress in the studies on the downstream signaling pathways of TNF-TNFR2 for controlling Treg homeostasis, differentiation and proliferation.
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22
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Li M, Zhang X, Bai X, Liang T. Targeting TNFR2: A Novel Breakthrough in the Treatment of Cancer. Front Oncol 2022; 12:862154. [PMID: 35494080 PMCID: PMC9048045 DOI: 10.3389/fonc.2022.862154] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 03/22/2022] [Indexed: 12/18/2022] Open
Abstract
Tumor necrosis factor (TNF) receptor type II (TNFR2) is expressed in various tumor cells and some immune cells, such as regulatory T cells and myeloid-derived suppressing cells. TNFR2 contributes a lot to the tumor microenvironment. For example, it directly promotes the occurrence and growth of some tumor cells, activates immunosuppressive cells, and supports immune escape. Existing studies have proved the importance of TNFR2 in cancer treatment. Here, we reviewed the activation mechanism of TNFR2 and its role in signal transduction in the tumor microenvironment. We summarized the expression and function of TNFR2 within different immune cells and the potential opportunities and challenges of targeting TNFR2 in immunotherapy. Finally, the advantages and limitations of TNFR2 to treat tumor-related diseases are discussed, and the problems that may be encountered in the clinical development and application of targeted anti-TNFR2 agonists and inhibitors are analyzed.
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Affiliation(s)
- Muchun Li
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Hangzhou, China
- Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Hangzhou, China
| | - Xiaozhen Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Hangzhou, China
- Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Hangzhou, China
| | - Xueli Bai
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Hangzhou, China
- Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Hangzhou, China
- *Correspondence: Tingbo Liang, ; Xueli Bai,
| | - Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Hangzhou, China
- Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
- *Correspondence: Tingbo Liang, ; Xueli Bai,
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Moatti A, Debesset A, Pilon C, Beldi-Ferchiou A, Leclerc M, Redjoul R, Charlotte F, To NH, Bak A, Belkacemi Y, Salomon BL, Issa F, Michonneau D, Maury S, Cohen JL, Thiolat A. TNFR2 blockade of regulatory T cells unleashes an antitumor immune response after hematopoietic stem-cell transplantation. J Immunother Cancer 2022; 10:jitc-2021-003508. [PMID: 35387779 PMCID: PMC8987798 DOI: 10.1136/jitc-2021-003508] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/01/2022] [Indexed: 12/13/2022] Open
Abstract
Background Targeting immune checkpoints that inhibit antitumor immune responses has emerged as a powerful new approach to treat cancer. We recently showed that blocking the tumor necrosis factor receptor-type 2 (TNFR2) pathway induces the complete loss of the protective function of regulatory T cells (Tregs) in a model of graft-versus-host disease (GVHD) prevention that relies on Treg-based cell therapy. Here, we tested the possibility of amplifying the antitumor response by targeting TNFR2 in a model of tumor relapse following hematopoietic stem-cell transplantation, a clinical situation for which the need for efficient therapeutic options is still unmet. Method We developed appropriate experimental conditions that mimic patients that relapsed from their initial hematological malignancy after hematopoietic stem-cell transplantation. This consisted of defining in allogeneic bone marrow transplantation models developed in mice, the maximum number of required tumor cells and T cells to infuse into recipient mice to develop a model of tumor relapse without inducing GVHD. We next evaluated whether anti-TNFR2 treatment could trigger alloreactivity and consequently antitumor immune response. In parallel, we also studied the differential expression of TNFR2 on T cells including Treg from patients in post-transplant leukemia relapse and in patients developing GVHD. Results Using experimental conditions in which neither donor T cells nor TNFR2-blocking antibody per se have any effect on tumor relapse, we observed that the coadministration of a suboptimal number of T cells and an anti-TNFR2 treatment can trigger alloreactivity and subsequently induce a significant antitumor effect. This was associated with a reduced percentage of activated CD4+ and CD8+ Tregs. Importantly, human Tregs over-expressed TNFR2 relative to conventional T cells in healthy donors and in patients experiencing leukemia relapse or cortico-resistant GVHD after hematopoietic stem cell transplantation. Conclusions These results highlight TNFR2 as a new target molecule for the development of immunotherapies to treat blood malignancy relapse, used either directly in grafted patients or to enhance donor lymphocyte infusion strategies. More widely, they open the door for new perspectives to amplify antitumor responses against solid cancers by directly targeting Tregs through their TNFR2 expression.
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Affiliation(s)
- Audrey Moatti
- INSERM, IMRB, Université Paris-Est Créteil Val de Marne, Créteil, France.,CIC Biotherapy, GHU Chenevier Mondor, Créteil, France
| | - Anais Debesset
- INSERM, IMRB, Université Paris-Est Créteil Val de Marne, Créteil, France
| | | | | | - Mathieu Leclerc
- INSERM, IMRB, Université Paris-Est Créteil Val de Marne, Créteil, France.,Service d'hématologie Clinique, GHU Chenevier Mondor, Créteil, France
| | - Rabah Redjoul
- Service d'hématologie Clinique, GHU Chenevier Mondor, Créteil, France
| | - Frederic Charlotte
- Service d'anatomopathologie, University Hospital Pitié Salpêtrière, Paris, France
| | - Nhu Hanh To
- INSERM, IMRB, Université Paris-Est Créteil Val de Marne, Créteil, France.,Service d'oncologie-radiothérapie, GHU Chenevier Mondor, Créteil, France
| | - Adeline Bak
- Service d'oncologie-radiothérapie, GHU Chenevier Mondor, Créteil, France
| | - Yazid Belkacemi
- INSERM, IMRB, Université Paris-Est Créteil Val de Marne, Créteil, France.,Service d'oncologie-radiothérapie, GHU Chenevier Mondor, Créteil, France
| | - Benoît Laurent Salomon
- INSERM, CNRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Sorbonne Université, Paris, France
| | - Fadi Issa
- Transplantation Research Immunology Group, University of Oxford Nuffield Department of Surgical Sciences, Oxford, UK
| | | | - Sebastien Maury
- INSERM, IMRB, Université Paris-Est Créteil Val de Marne, Créteil, France.,Service d'hématologie Clinique, GHU Chenevier Mondor, Créteil, France
| | - José Laurent Cohen
- INSERM, IMRB, Université Paris-Est Créteil Val de Marne, Créteil, France .,CIC Biotherapy, GHU Chenevier Mondor, Créteil, France
| | - Allan Thiolat
- INSERM, IMRB, Université Paris-Est Créteil Val de Marne, Créteil, France
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Kato M, Imaizumi N, Tanaka R, Mizuguchi M, Hayashi M, Miyagi T, Uchihara J, Ohshiro K, Todoroki J, Karube K, Masuzaki H, Tanaka Y, Fukushima T. Elevation of the Plasma Levels of TNF Receptor 2 in Association with Those of CD25, OX40, and IL-10 and HTLV-1 Proviral Load in Acute Adult T-Cell Leukemia. Viruses 2022; 14:v14040751. [PMID: 35458481 PMCID: PMC9032861 DOI: 10.3390/v14040751] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 03/26/2022] [Accepted: 03/29/2022] [Indexed: 12/26/2022] Open
Abstract
Adult T-cell leukemia/lymphoma (ATL) cells express TNF receptor type-2 (TNFR2) on their surface and shed its soluble form (sTNFR2). We previously reported that sTNFR2 levels were highly elevated in the plasma of patients with acute ATL. To investigate whether its quantitation would be helpful for the diagnosis or prediction of the onset of acute ATL, we examined the plasma levels of sTNFR2 in a large number of specimens obtained from a cohort of ATL patients and asymptomatic human T-cell leukemia virus type 1 (HTLV-1) carriers (ACs) and compared them to those of other candidate ATL biomarkers (sCD25, sOX40, and IL-10) by enzyme-linked immunosorbent assays (ELISA) and HTLV-1 proviral loads. We observed that sTNFR2 levels were significantly elevated in acute ATL patients compared to ACs and patients with other types of ATL (chronic, smoldering, and lymphoma). Importantly, sTNFR2 levels were significantly correlated with those of sCD25, sOX40, and IL-10, as well as proviral loads. Thus, the present study confirmed that an increase in plasma sTNFR2 levels is a biomarker for the diagnosis of acute ATL. Examination of plasma sTNFR2 alone or in combination with other ATL biomarkers may be helpful for the diagnosis of acute ATL.
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Affiliation(s)
- Megumi Kato
- Laboratory of Hematoimmunology, Graduate School of Health Sciences, University of the Ryukyus, Nishihara 903-0215, Japan; (M.K.); (R.T.)
| | - Naoki Imaizumi
- Laboratory of Molecular Genetics, Graduate School of Health Sciences, University of the Ryukyus, Nishihara 903-0215, Japan;
| | - Reiko Tanaka
- Laboratory of Hematoimmunology, Graduate School of Health Sciences, University of the Ryukyus, Nishihara 903-0215, Japan; (M.K.); (R.T.)
| | - Mariko Mizuguchi
- Department of Investigative Medicine, Graduate School of Medicine, University of the Ryukyus, Nishihara 903-0215, Japan;
| | - Masaki Hayashi
- Department of Hematology, Nakagami Hospital, Okinawa 904-2142, Japan;
| | - Takashi Miyagi
- Department of Hematology, Heart Life Hospital, Nakagusuku 901-2492, Japan;
| | | | - Kazuiku Ohshiro
- Department of Hematology, Okinawa Prefectural Nambu Medical Center and Children’s Medical Center, Naha 901-1193, Japan;
| | - Junpei Todoroki
- Department of Hematology, Chubu Tokushukai Hospital, Nakagami 901-2305, Japan;
| | - Kennosuke Karube
- Department of Pathology and Laboratory Medicine, Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan;
| | - Hiroaki Masuzaki
- Division of Endocrinology, Diabetes, and Metabolism, Hematology, Rheumatology, Second Department of Internal Medicine, Graduate School of Medicine, University of the Ryukyus, Nishihara 903-0215, Japan;
| | - Yuetsu Tanaka
- Laboratory of Hematoimmunology, Graduate School of Health Sciences, University of the Ryukyus, Nishihara 903-0215, Japan; (M.K.); (R.T.)
- Correspondence: (Y.T.); (T.F.); Tel.: +81-98-895-1745 (Y.T.); +81-98-895-1276 (T.F.)
| | - Takuya Fukushima
- Laboratory of Hematoimmunology, Graduate School of Health Sciences, University of the Ryukyus, Nishihara 903-0215, Japan; (M.K.); (R.T.)
- Correspondence: (Y.T.); (T.F.); Tel.: +81-98-895-1745 (Y.T.); +81-98-895-1276 (T.F.)
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25
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Chen Y, Jia M, Wang S, Xu S, He N. Antagonistic Antibody Targeting TNFR2 Inhibits Regulatory T Cell Function to Promote Anti-Tumor Activity. Front Immunol 2022; 13:835690. [PMID: 35251028 PMCID: PMC8889907 DOI: 10.3389/fimmu.2022.835690] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 01/26/2022] [Indexed: 12/12/2022] Open
Abstract
Infiltration of regulatory T cells (Tregs) in the tumor microenvironment suppresses anti-tumor immune response, and promotes tumor progression. Tumor necrosis factor receptor-2 (TNFR2), which is highly expressed on Tregs, activates Tregs through nuclear factor kappa B (NF-κB) pathway. Moreover, TNFR2+ Tregs have been shown to be most suppressive among all Tregs populations in tumor. Due to the unique expression pattern and function of TNFR2 on Tregs, a TNFR2 blocking antibody is expected to compromise Tregs function, relieve Tregs-mediated immunosuppression, and hence to enhance anti-tumor immune response. AN3025 is an antagonistic anti-human TNFR2 (hTNFR2) antibody that is currently under preclinical development. This study investigates the immunomodulatory and anti-tumor activity of AN3025. AN3025 was generated through rabbit immunization with extracellular domain of human TNFR2 and subsequent humanization by complementarity-determining regions (CDRs) grafting. AN3025 binds to the extracellular domain of both human and cynomolgus with sub-nanomolar affinity and specificity, but not mouse or rat TNFR2. AN3025 inhibited tumor necrosis factor alpha (TNFα) induced cell death of hTNFR2-overexpressing Jurkat cells by competing with TNFα for binding to hTNFR2. In the Tregs/T effector co-culture assay, AN3025 increased T effector proliferation and enhanced interferon gamma (IFNγ) production. As a monotherapy, AN3025 significantly inhibited MC38 tumor growth in TNFR2 humanized mouse model. Subsequent flow cytometry (FACS) and immunohistochemistry (IHC) analysis revealed that administration of AN3025 led to decreased Tregs population, increased CD4+ and CD8+ T cell numbers in the tumor. The anti-tumor activity of AN3025 was dependent on the existence of CD4+ and CD8+ T cells, as depletion of CD4+ and CD8+ T cells abolished the anti-tumor activity of AN3025. In addition, AN3025 in combination with anti-PD-1 antibody demonstrated stronger in-vivo anti-tumor activity. The potent anti-tumor efficacy of AN3025, either as a monotherapy or in combination with anti-PD-1 antibody, supports its further clinical development for the treatment of various human tumors.
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Affiliation(s)
- Yonglin Chen
- Department of Biosciences, Adlai Nortye USA Inc., North Brunswick, NJ, United States
| | - Manxue Jia
- Department of Biosciences, Adlai Nortye USA Inc., North Brunswick, NJ, United States
| | - Sharon Wang
- Department of Biosciences, Adlai Nortye USA Inc., North Brunswick, NJ, United States
| | - Sherry Xu
- Department of Biosciences, Adlai Nortye USA Inc., North Brunswick, NJ, United States
| | - Nanhai He
- Department of Biosciences, Adlai Nortye USA Inc., North Brunswick, NJ, United States
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26
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Zhang X, Lao M, Xu J, Duan Y, Yang H, Li M, Ying H, He L, Sun K, Guo C, Chen W, Jiang H, Zhang X, Bai X, Liang T. Combination cancer immunotherapy targeting TNFR2 and PD-1/PD-L1 signaling reduces immunosuppressive effects in the microenvironment of pancreatic tumors. J Immunother Cancer 2022; 10:e003982. [PMID: 35260434 PMCID: PMC8906048 DOI: 10.1136/jitc-2021-003982] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/24/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUNDS In advanced pancreatic ductal adenocarcinoma (PDAC), immune therapy, including immune checkpoint inhibitors, has limited efficacy, encouraging the study of combination therapy. METHODS Tumor necrosis factor receptor 2 (TNFR2) was analyzed via immunohistochemistry, immunofluorescence, western blotting, and ELISAs. The in vitro mechanism that TNFR2 regulates programmed cell death 1 ligand 1 (PD-L1) was investigated using immunofluorescence, immunohistochemistry, flow cytometry, western blotting, and chromatin immunoprecipitation (ChIP). In vivo efficacy and mechanistic studies, using C57BL/6 mice and nude mice with KPC cell-derived subcutaneous and orthotopic tumors, employed antibodies against TNFR2 and PD-L1. Survival curves were constructed for the orthotopic model and a genetically engineered PDAC model (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre). Mass cytometry, immunohistochemistry, and flow cytometry analyzed local and systemic alterations in the immunophenotype. RESULTS TNFR2 showed high expression and is a prognostic factor in CD8+ T cell-enriched pancreatic cancer. TNFR2 promotes tumorigenesis and progression of pancreatic cancer via dual effect: suppressing cancer immunogenicity and partially accelerating tumor growth. TNFR2 positivity correlated with PD-L1, and in vitro and in vivo, it could regulate the expression of PDL1 at the transcription level via the p65 NF-κB pathway. Combining anti-TNFR2 and PD-L1 antibodies eradicated tumors, prolonged overall survival in pancreatic cancer, and induced strong antitumor immune memory and secondary prevention by reducing the infiltration of Tregs and tumor-associated macrophages and inducing CD8+ T cell activation in the PDAC microenvironment. Finally, the antitumor immune response derived from combination therapy is mainly dependent on CD8+ T cells, partially dependent on CD4+ T cells, and independent of natural killer cells. CONCLUSIONS Anti-TNFR2 and anti-PD-L1 combination therapy eradicated tumors by inhibiting their growth, relieving tumor immunosuppression, and generating robust memory recall.
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Affiliation(s)
- Xiaozhen Zhang
- Department of Hepatobiliary and Pancreatic Surgery,the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Zhejiang University, Hangzhou, China
| | - Mengyi Lao
- Department of Hepatobiliary and Pancreatic Surgery,the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Zhejiang University, Hangzhou, China
| | - Jian Xu
- Department of Hepatobiliary and Pancreatic Surgery,the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Zhejiang University, Hangzhou, China
| | - Yi Duan
- Department of Hepatobiliary and Pancreatic Surgery,the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Zhejiang University, Hangzhou, China
| | - Hanshen Yang
- Department of Hepatobiliary and Pancreatic Surgery,the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Zhejiang University, Hangzhou, China
| | - Muchun Li
- Department of Hepatobiliary and Pancreatic Surgery,the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Zhejiang University, Hangzhou, China
| | - Honggang Ying
- Department of Hepatobiliary and Pancreatic Surgery,the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Zhejiang University, Hangzhou, China
| | - Lihong He
- Department of Hepatobiliary and Pancreatic Surgery,the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Zhejiang University, Hangzhou, China
| | - Kang Sun
- Department of Hepatobiliary and Pancreatic Surgery,the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Zhejiang University, Hangzhou, China
| | - Chengxiang Guo
- Department of Hepatobiliary and Pancreatic Surgery,the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Zhejiang University, Hangzhou, China
| | - Wen Chen
- Department of Hepatobiliary and Pancreatic Surgery,the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Zhejiang University, Hangzhou, China
| | - Haitao Jiang
- Department of Hepatobiliary and Pancreatic Surgery,the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Zhejiang University, Hangzhou, China
| | - Xiaoyu Zhang
- Department of Hepatobiliary and Pancreatic Surgery,the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Zhejiang University, Hangzhou, China
| | - Xueli Bai
- Department of Hepatobiliary and Pancreatic Surgery,the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Zhejiang University, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery,the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Zhejiang University, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
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Jiang M, Liu J, Yang D, Tross D, Li P, Chen F, Alam MM, Faustman DL, Oppenheim JJ, Chen X. A TNFR2 antibody by countering immunosuppression cooperates with HMGN1 and R848 immune stimulants to inhibit murine colon cancer. Int Immunopharmacol 2021; 101:108345. [PMID: 34794079 DOI: 10.1016/j.intimp.2021.108345] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Revised: 11/02/2021] [Accepted: 11/02/2021] [Indexed: 12/31/2022]
Abstract
Immunosuppressive CD4+Foxp3+ regulatory T cells (Tregs) promote tumor immune evasion and thus targeting of Tregs has become an strategy in cancer immunotherapy. Tumor necrosis factor receptor 2 (TNFR2) is highly expressed and important for the immunosuppressive function of Tregs in humans and mice. Thus, the benefit of targeting TNFR2 in cancer immunotherapy merits more investigation. A previous report identified a new murine monoclonal anti-TNFR2 antibody (designated TY101), which showed therapeutic efficacy in murine cancer models, but its mechanism of action was less understood. In this study, the capacity of a combination of immunostimulants to enhance the effect of this inhibitor of Tregs was investigated. We examined the efficacy of TY101 as an anti-tumor immune reagent combined with HMGN1 (N1, a dendritic cell activating TLR4 agonist) and R848 (a synthetic TLR7/8 agonist). This immunotherapeutic combination exerted synergistic antitumor effects as compared with any single treatment. The antitumor response was mainly mediated by the depletion of Tregs and stimulation of cytotoxic CD8 T cell activation. The result also suggested that the effect of TY101 was similar to that of anti-PD-L1 when used in combination with these immunostimulants. Therefore, we propose that treatment strategies of antagonizing TNFR2 on Tregs would behave as potent checkpoint inhibitors and can potentially be utilized to develop a novel antitumor immunotherapy.
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Affiliation(s)
- Mengmeng Jiang
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macau SAR 999078, China
| | - Jia Liu
- Laboratory of Cancer Immunometabolism, Center for Cancer Research, National Cancer Institute at Frederick, NIH, Frederick, MD, USA; Department of Pharmacy, Changchun University of Chinese Medicine, Changchun, Jilin 130117, China
| | - De Yang
- Laboratory of Cancer Immunometabolism, Center for Cancer Research, National Cancer Institute at Frederick, NIH, Frederick, MD, USA
| | - Debra Tross
- Laboratory of Cancer Immunometabolism, Center for Cancer Research, National Cancer Institute at Frederick, NIH, Frederick, MD, USA
| | - Ping Li
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macau SAR 999078, China
| | - Fengyang Chen
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macau SAR 999078, China
| | - Md Masud Alam
- Laboratory of Cancer Immunometabolism, Center for Cancer Research, National Cancer Institute at Frederick, NIH, Frederick, MD, USA
| | - Denise L Faustman
- Immunobiology Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Joost J Oppenheim
- Laboratory of Cancer Immunometabolism, Center for Cancer Research, National Cancer Institute at Frederick, NIH, Frederick, MD, USA.
| | - Xin Chen
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macau SAR 999078, China; Department of Pharmaceutical Science, Faculty of Health Sciences, University of Macau, Macau SAR 999078, China; MoE Frontiers Science Center for Precision Oncology, University of Macau, Macau SAR 999078, China; Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, China.
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28
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Moatti A, Cohen JL. The TNF-α/TNFR2 Pathway: Targeting a Brake to Release the Anti-tumor Immune Response. Front Cell Dev Biol 2021; 9:725473. [PMID: 34712661 PMCID: PMC8546260 DOI: 10.3389/fcell.2021.725473] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 09/24/2021] [Indexed: 12/15/2022] Open
Abstract
Newly discovered anti-cancer immunotherapies, such as immune checkpoint inhibitors and chimeric antigen receptor T cells, focus on spurring the anti-tumor effector T cell (Teff) response. Although such strategies have already demonstrated a sustained beneficial effect in certain malignancies, a substantial proportion of treated patients does not respond. CD4+FOXP3+ regulatory T cells (Tregs), a suppressive subset of T cells, can impair anti-tumor responses and reduce the efficacy of currently available immunotherapies. An alternative view that has emerged over the last decade proposes to tackle this immune brake by targeting the suppressive action of Tregs on the anti-tumoral response. It was recently demonstrated that the tumor necrosis factor alpha (TNF-α) tumor necrosis factor receptor 2 (TNFR2) is critical for the phenotypic stabilization and suppressive function of human and mouse Tregs. The broad non-specific effects of TNF-α infusion in patients initially led clinicians to abandon this signaling pathway as first-line therapy against neoplasms. Previously unrecognized, TNFR2 has emerged recently as a legitimate target for anti-cancer immune checkpoint therapy. Considering the accumulation of pre-clinical data on the role of TNFR2 and clinical reports of TNFR2+ Tregs and tumor cells in cancer patients, it is now clear that a TNFR2-centered approach could be a viable strategy, once again making the TNF-α pathway a promising anti-cancer target. Here, we review the role of the TNFR2 signaling pathway in tolerance and the equilibrium of T cell responses and its connections with oncogenesis. We analyze recent discoveries concerning the targeting of TNFR2 in cancer, as well as the advantages, limitations, and perspectives of such a strategy.
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Affiliation(s)
- Audrey Moatti
- Université Paris-Est Créteil Val de Marne, INSERM, IMRB, Créteil, France.,AP-HP, Groupe Hospitalo-Universitaire Chenevier Mondor, Centre d'Investigation Clinique Biothérapie, Créteil, France
| | - José L Cohen
- Université Paris-Est Créteil Val de Marne, INSERM, IMRB, Créteil, France.,AP-HP, Groupe Hospitalo-Universitaire Chenevier Mondor, Centre d'Investigation Clinique Biothérapie, Créteil, France
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Razazian M, Khosravi M, Bahiraii S, Uzan G, Shamdani S, Naserian S. Differences and similarities between mesenchymal stem cell and endothelial progenitor cell immunoregulatory properties against T cells. World J Stem Cells 2021; 13:971-984. [PMID: 34567420 PMCID: PMC8422932 DOI: 10.4252/wjsc.v13.i8.971] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 04/28/2021] [Accepted: 07/16/2021] [Indexed: 02/06/2023] Open
Abstract
Bone-marrow-derived mesenchymal stem cells and endothelial progenitor cells have some interesting biological properties that make them unique for cell therapy of degenerative and cardiovascular disorders. Although both cell populations have been already studied and used for their regenerative potentials, recently their special immunoregulatory features have brought much more attention. Mesenchymal stem cells and endothelial progenitor cells have both proangiogenic functions and have been shown to suppress the immune response, particularly T cell proliferation, activation, and cytokine production. This makes them suitable choices for allogeneic stem cell transplantation. Nevertheless, these two cells do not have equal immunoregulatory activities. Many elements including their extraction sources, age/passage, expression of different markers, secretion of bioactive mediators, and some others could change the efficiency of their immunosuppressive function. However, to our knowledge, no publication has yet compared mesenchymal stem cells and endothelial progenitor cells for their immunological interaction with T cells. This review aims to specifically compare the immunoregulatory effect of these two populations including their T cell suppression, deactivation, cytokine production, and regulatory T cells induction capacities. Moreover, it evaluates the implications of the tumor necrosis factor alpha-tumor necrosis factor receptor 2 axis as an emerging immune checkpoint signaling pathway controlling most of their immunological properties.
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Affiliation(s)
- Mehdi Razazian
- Institut national de la santé et de la recherche médicale (Inserm) Unité Mixte de Recherche-Inserm-Ministère de la Défense 1197, Hôpital Paul Brousse, Villejuif 94800, France
| | - Maryam Khosravi
- Microenvironment & Immunity Unit, Institut Pasteur, Paris 75724, France
- Institut national de la santé et de la recherche médicale (Inserm) Unit 1224, Paris 75724, France
| | - Sheyda Bahiraii
- Department of Pharmacognosy, University of Vienna, Vienna 1090, Austria
| | - Georges Uzan
- Institut national de la santé et de la recherche médicale (Inserm) Unité Mixte de Recherche-Inserm-Ministère de la Défense 1197, Hôpital Paul Brousse, Villejuif 94800, France
- Paris-Saclay University, Villejuif 94800, France
| | - Sara Shamdani
- Institut national de la santé et de la recherche médicale (Inserm) Unité Mixte de Recherche-Inserm-Ministère de la Défense 1197, Hôpital Paul Brousse, Villejuif 94800, France
- Paris-Saclay University, Villejuif 94800, France
- CellMedEx; Saint Maur Des Fossés 94100, France
| | - Sina Naserian
- Institut national de la santé et de la recherche médicale (Inserm) Unité Mixte de Recherche-Inserm-Ministère de la Défense 1197, Hôpital Paul Brousse, Villejuif 94800, France
- Paris-Saclay University, Villejuif 94800, France
- CellMedEx; Saint Maur Des Fossés 94100, France.
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Transmembrane TNF and Its Receptors TNFR1 and TNFR2 in Mycobacterial Infections. Int J Mol Sci 2021; 22:ijms22115461. [PMID: 34067256 PMCID: PMC8196896 DOI: 10.3390/ijms22115461] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 05/12/2021] [Accepted: 05/17/2021] [Indexed: 12/16/2022] Open
Abstract
Tumor necrosis factor (TNF) is one of the main cytokines regulating a pro-inflammatory environment. It has been related to several cell functions, for instance, phagocytosis, apoptosis, proliferation, mitochondrial dynamic. Moreover, during mycobacterial infections, TNF plays an essential role to maintain granuloma formation. Several effector mechanisms have been implicated according to the interactions of the two active forms, soluble TNF (solTNF) and transmembrane TNF (tmTNF), with their receptors TNFR1 and TNFR2. We review the impact of these interactions in the context of mycobacterial infections. TNF is tightly regulated by binding to receptors, however, during mycobacterial infections, upstream activation signalling pathways may be influenced by key regulatory factors either at the membrane or cytosol level. Detailing the structure and activation pathways used by TNF and its receptors, such as its interaction with solTNF/TNFRs versus tmTNF/TNFRs, may bring a better understanding of the molecular mechanisms involved in activation pathways which can be helpful for the development of new therapies aimed at being more efficient against mycobacterial infections.
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Proteomic profiling of HTLV-1 carriers and ATL patients reveals sTNFR2 as a novel diagnostic biomarker for acute ATL. Blood Adv 2021; 4:1062-1071. [PMID: 32196559 DOI: 10.1182/bloodadvances.2019001429] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Accepted: 02/23/2020] [Indexed: 12/25/2022] Open
Abstract
Adult T-cell leukemia/lymphoma (ATL) is a human T-cell leukemia virus type 1 (HTLV-1)-associated T-cell malignancy with generally poor prognosis. Although only ∼5% of HTLV-1 carriers progress to ATL, early diagnosis is challenging because of the lack of ATL biomarkers. In this study, we analyzed blood plasma profiles of asymptomatic HTLV-1 carriers (ACs); untreated ATL patients, including acute, lymphoma, smoldering, and chronic types; and ATL patients in remission. Through SOMAscan, expression levels of 1305 plasma proteins were analyzed in 85 samples (AC, n = 40; ATL, n = 40; remission, n = 5). Using gene set enrichment analysis and gene ontology, overrepresented pathways in ATL vs AC included angiogenesis, inflammation by cytokines and chemokines, interleukin-6 (IL-6)/JAK/STAT3, and notch signaling. In selecting candidate biomarkers, we focused on soluble tumor necrosis factor 2 (sTNFR2) because of its active role in enriched pathways, extreme significance (Welch's t test P < .00001), high discrimination capacity (area under the curve >0.90), and novelty in ATL research. Quantification of sTNFR2 in 102 plasma samples (AC, n = 30; ATL, n = 68; remission, n = 4) using enzyme-linked immunosorbent assay showed remarkable elevations in acute ATL, at least 10 times those of AC samples, and return of sTNFR2 to AC state levels after achieving remission. Flow cytometry and immunostaining validated the expression of TNFR2 in ATL cells. No correlation between sIL-2 and sTNFR2 levels in acute ATL was found, suggesting the possibility of sTNFR2 as an independent biomarker. Our findings represent the first extensive blood-based proteomic analysis of ATL, suggesting the potential clinical utility of sTNFR2 in diagnosing acute ATL.
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Yang Y, Islam MS, Hu Y, Chen X. TNFR2: Role in Cancer Immunology and Immunotherapy. Immunotargets Ther 2021; 10:103-122. [PMID: 33907692 PMCID: PMC8071081 DOI: 10.2147/itt.s255224] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 02/16/2021] [Indexed: 12/17/2022] Open
Abstract
Immune checkpoint inhibitors (ICIs), including anti-CTLA-4 (cytotoxic T lymphocyte antigen-4) and anti-PD-1/PD-L1 (programmed death-1/programmed death-ligand 1), represent a turning point in the cancer immunotherapy. However, only a minor fraction of patients could derive benefit from such therapy. Therefore, new strategies targeting additional immune regulatory mechanisms are urgently needed. CD4+Foxp3+ regulatory T cells (Tregs) represent a major cellular mechanism in cancer immune evasion. There is compelling evidence that tumor necrosis factor (TNF) receptor type II (TNFR2) plays a decisive role in the activation and expansion of Tregs and other types of immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs). Furthermore, TNFR2 is also expressed by some tumor cells. Emerging experimental evidence indicates that TNFR2 may be a therapeutic target to enhance naturally occurring or immunotherapeutic-triggered anti-tumor immune responses. In this article, we discuss recent advances in the understanding of the mechanistic basis underlying the Treg-boosting effect of TNFR2. The role of TNFR2-expressing highly suppressive Tregs in tumor immune evasion and their possible contribution to the non-responsiveness to checkpoint treatment are analyzed. Moreover, the role of TNFR2 expression on tumor cells and the impact of TNFR2 signaling on other types of cells that shape the immunological landscape in the tumor microenvironment, such as MDSCs, MSCs, ECs, EPCs, CD8+ CTLs, and NK cells, are also discussed. The reports revealing the effect of TNFR2-targeting pharmacological agents in the experimental cancer immunotherapy are summarized. We also discuss the potential opportunities and challenges for TNFR2-targeting immunotherapy.
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Affiliation(s)
- Yang Yang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, SAR, 999078, People's Republic of China
| | - Md Sahidul Islam
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, SAR, 999078, People's Republic of China
| | - Yuanjia Hu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, SAR, 999078, People's Republic of China
| | - Xin Chen
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, SAR, 999078, People's Republic of China
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Recruitment and Expansion of Tregs Cells in the Tumor Environment-How to Target Them? Cancers (Basel) 2021; 13:cancers13081850. [PMID: 33924428 PMCID: PMC8069615 DOI: 10.3390/cancers13081850] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 04/04/2021] [Accepted: 04/08/2021] [Indexed: 12/22/2022] Open
Abstract
Simple Summary The immune response against cancer is generated by effector T cells, among them cytotoxic CD8+ T cells that destroy cancer cells and helper CD4+ T cells that mediate and support the immune response. This antitumor function of T cells is tightly regulated by a particular subset of CD4+ T cells, named regulatory T cells (Tregs), through different mechanisms. Even if the complete inhibition of Tregs would be extremely harmful due to their tolerogenic role in impeding autoimmune diseases in the periphery, the targeted blockade of their accumulation at tumor sites or their targeted depletion represent a major therapeutic challenge. This review focuses on the mechanisms favoring Treg recruitment, expansion and stabilization in the tumor microenvironment and the therapeutic strategies developed to block these mechanisms. Abstract Regulatory T cells (Tregs) are present in a large majority of solid tumors and are mainly associated with a poor prognosis, as their major function is to inhibit the antitumor immune response contributing to immunosuppression. In this review, we will investigate the mechanisms involved in the recruitment, amplification and stability of Tregs in the tumor microenvironment (TME). We will also review the strategies currently developed to inhibit Tregs’ deleterious impact in the TME by either inhibiting their recruitment, blocking their expansion, favoring their plastic transformation into other CD4+ T-cell subsets, blocking their suppressive function or depleting them specifically in the TME to avoid severe deleterious effects associated with Treg neutralization/depletion in the periphery and normal tissues.
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Gubernatorova EO, Polinova AI, Petropavlovskiy MM, Namakanova OA, Medvedovskaya AD, Zvartsev RV, Telegin GB, Drutskaya MS, Nedospasov SA. Dual Role of TNF and LTα in Carcinogenesis as Implicated by Studies in Mice. Cancers (Basel) 2021; 13:1775. [PMID: 33917839 PMCID: PMC8068266 DOI: 10.3390/cancers13081775] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 03/30/2021] [Accepted: 04/02/2021] [Indexed: 02/07/2023] Open
Abstract
Tumor necrosis factor (TNF) and lymphotoxin alpha (LTα) are two related cytokines from the TNF superfamily, yet they mediate their functions in soluble and membrane-bound forms via overlapping, as well as distinct, molecular pathways. Their genes are encoded within the major histocompatibility complex class III cluster in close proximity to each other. TNF is involved in host defense, maintenance of lymphoid tissues, regulation of cell death and survival, and antiviral and antibacterial responses. LTα, known for some time as TNFβ, has pleiotropic functions including control of lymphoid tissue development and homeostasis cross talk between lymphocytes and their environment, as well as lymphoid tissue neogenesis with formation of lymphoid follicles outside the lymph nodes. Along with their homeostatic functions, deregulation of these two cytokines may be associated with initiation and progression of chronic inflammation, autoimmunity, and tumorigenesis. In this review, we summarize the current state of knowledge concerning TNF/LTα functions in tumor promotion and suppression, with the focus on the recently uncovered significance of host-microbiota interplay in cancer development that may explain some earlier controversial results.
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Affiliation(s)
- Ekaterina O. Gubernatorova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (A.I.P.); (M.M.P.); (O.A.N.); (A.D.M.); (R.V.Z.)
- Department of Immunology, Faculty of Biology, Lomonosov Moscow State University, 119234 Moscow, Russia
| | - Almina I. Polinova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (A.I.P.); (M.M.P.); (O.A.N.); (A.D.M.); (R.V.Z.)
- Department of Immunology, Faculty of Biology, Lomonosov Moscow State University, 119234 Moscow, Russia
| | - Mikhail M. Petropavlovskiy
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (A.I.P.); (M.M.P.); (O.A.N.); (A.D.M.); (R.V.Z.)
- Department of Immunology, Faculty of Biology, Lomonosov Moscow State University, 119234 Moscow, Russia
| | - Olga A. Namakanova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (A.I.P.); (M.M.P.); (O.A.N.); (A.D.M.); (R.V.Z.)
- Department of Immunology, Faculty of Biology, Lomonosov Moscow State University, 119234 Moscow, Russia
| | - Alexandra D. Medvedovskaya
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (A.I.P.); (M.M.P.); (O.A.N.); (A.D.M.); (R.V.Z.)
- Department of Immunology, Faculty of Biology, Lomonosov Moscow State University, 119234 Moscow, Russia
| | - Ruslan V. Zvartsev
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (A.I.P.); (M.M.P.); (O.A.N.); (A.D.M.); (R.V.Z.)
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - Georgij B. Telegin
- Branch of Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences (BIBCh, RAS), 142290 Pushchino, Russia;
| | - Marina S. Drutskaya
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (A.I.P.); (M.M.P.); (O.A.N.); (A.D.M.); (R.V.Z.)
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - Sergei A. Nedospasov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (A.I.P.); (M.M.P.); (O.A.N.); (A.D.M.); (R.V.Z.)
- Department of Immunology, Faculty of Biology, Lomonosov Moscow State University, 119234 Moscow, Russia
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
- Sirius University of Science and Technology, Federal Territory Sirius, 354340 Krasnodarsky Krai, Russia
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Abstract
Immune checkpoint inhibitors (ICIs) are effective in the treatment of patients with advanced cancer and have emerged as a pillar of standard cancer care. However, their use is complicated by adverse effects known as immune-related adverse events (irAEs), including ICI-induced inflammatory arthritis. ICI-induced inflammatory arthritis is distinguished from other irAEs by its persistence and requirement for long-term treatment. TNF inhibitors are commonly used to treat inflammatory diseases such as rheumatoid arthritis, spondyloarthropathies and inflammatory bowel disease, and have also been adopted as second-line agents to treat irAEs refractory to glucocorticoid treatment. Experiencing an irAE is associated with a better antitumour response after ICI treatment. However, whether TNF inhibition can be safely used to treat irAEs without promoting cancer progression, either by compromising ICI therapy efficacy or via another route, remains an open question. In this Review, we discuss clinical and preclinical studies that address the relationship between TNF, TNF inhibition and cancer. The bulk of the evidence suggests that at least short courses of TNF inhibitors are safe for the treatment of irAEs in patients with cancer undergoing ICI therapy. Data from preclinical studies hint that TNF inhibition might augment the antitumour effect of ICI therapy while simultaneously ameliorating irAEs.
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TNF-TNFR2 Signal Plays a Decisive Role in the Activation of CD4 +Foxp3 + Regulatory T Cells: Implications in the Treatment of Autoimmune Diseases and Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1278:257-272. [PMID: 33523452 DOI: 10.1007/978-981-15-6407-9_13] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The puzzling biphasic or dual roles of tumor necrosis factor α (TNF) in the inflammatory and immune responses are likely to be mediated by distinct signaling pathways transduced by one of its two receptors, e.g., TNF receptor type I (TNFR1) and TNF receptor type II (TNFR2). Unlike TNFR1 that is ubiquitously expressed on almost all types of cells, the expression of TNFR2 is rather restricted to certain types of cells, such as T lymphocytes. There is now compelling evidence that TNFR2 is preferentially expressed by CD4+Foxp3+ regulatory T cells (Tregs), and TNFR2 plays a decisive role in the activation, expansion, in vivo function, and phenotypical stability of Tregs. In this chapter, the current understanding of the molecular basis and signaling pathway of TNF-TNFRs signal is introduced. Latest studies that have further supported and substantiated the pivotal role of TNF-TNFR2 interaction in Tregs biology and its molecular basis are discussed. The research progress regarding TNFR2-targeting treatment for autoimmune diseases and cancer is analyzed. Future study should focus on the further understanding of molecular mechanism underlying Treg-stimulatory effect of TNFR2 signal, as well as on the translation of research findings into therapeutic benefits of human patients with autoimmune diseases, allergy, allograft rejection, and cancer.
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Torrey H, Kühtreiber WM, Okubo Y, Tran L, Case K, Zheng H, Vanamee E, Faustman DL. A novel TNFR2 agonist antibody expands highly potent regulatory T cells. Sci Signal 2020; 13:13/661/eaba9600. [DOI: 10.1126/scisignal.aba9600] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Affiliation(s)
- Heather Torrey
- Immunobiology Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA
| | - Willem M. Kühtreiber
- Immunobiology Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA
| | - Yoshiaki Okubo
- Immunobiology Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA
| | - Lisa Tran
- Immunobiology Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA
| | - Katherine Case
- Immunobiology Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA
| | - Hui Zheng
- Immunobiology Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA
| | - Eva Vanamee
- Immunobiology Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA
| | - Denise L. Faustman
- Immunobiology Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA
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Patel PM, Jones VA, Kridin K, Amber KT. The role of Dipeptidyl Peptidase-4 in cutaneous disease. Exp Dermatol 2020; 30:304-318. [PMID: 33131073 DOI: 10.1111/exd.14228] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 09/21/2020] [Accepted: 10/26/2020] [Indexed: 12/14/2022]
Abstract
Dipeptidyl peptidase-4 (DPP4) is a multifunctional, transmembrane glycoprotein present on the cell surface of various tissues. It is present in multiple molecular forms including cell surface and soluble. The role of DPP4 and its inhibition in cutaneous dermatoses have been a recent point of investigation. DPP4 exerts a notable influence on T-cell biology, the induction of skin-specific lymphocytes, and the homeostasis between regulatory and effector T cells. Moreover, DPP4 interacts with a broad range of molecules, including adenosine deaminase, caveolin-1, CXCR4 receptor, M6P/insulin-like growth factor II-receptor and fibroblast activation protein-α, triggering downstream effects that modulate the immune response, cell adhesion and chemokine activity. DPP4 expression on melanocytes, keratinocytes and fibroblasts further alters cell function and, thus, has crucial implications in cutaneous pathology. As a result, DPP4 plays a significant role in bullous pemphigoid, T helper type 1-like reactions, cutaneous lymphoma, melanoma, wound healing and fibrotic disorders. This review illustrates the multifactorial role of DPP4 expression, regulation, and inhibition in cutaneous diseases.
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Affiliation(s)
- Payal M Patel
- Department of Dermatology, University of Illinois at Chicago, Chicago, IL, USA
| | - Virginia A Jones
- Department of Dermatology, University of Illinois at Chicago, Chicago, IL, USA
| | - Khalaf Kridin
- Department of Dermatology, University of Lübeck, Lübeck, Germany
| | - Kyle T Amber
- Department of Dermatology, University of Illinois at Chicago, Chicago, IL, USA
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Beldi G, Khosravi M, Abdelgawad ME, Salomon BL, Uzan G, Haouas H, Naserian S. TNFα/TNFR2 signaling pathway: an active immune checkpoint for mesenchymal stem cell immunoregulatory function. Stem Cell Res Ther 2020; 11:281. [PMID: 32669116 PMCID: PMC7364521 DOI: 10.1186/s13287-020-01740-5] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 04/30/2020] [Accepted: 05/25/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND In addition to their multilineage potential, mesenchymal stem cells (MSCs) have a broad range of functions from tissue regeneration to immunomodulation. MSCs have the ability to modulate the immune response and change the progression of different inflammatory and autoimmune disorders. However, there are still many challenges to overcome before their widespread clinical administration including the mechanisms behind their immunoregulatory function. MSCs inhibit effector T cells and other immune cells, while inducing regulatory T cells (T regs), thus, reducing directly and indirectly the production of pro-inflammatory cytokines. TNF/TNFR signaling plays a dual role: while the interaction of TNFα with TNFR1 mediates pro-inflammatory effects and cell death, its interaction with TNFR2 mediates anti-inflammatory effects and cell survival. Many immunosuppressive cells like T regs, regulatory B cells (B regs), endothelial progenitor cells (EPCs), and myeloid-derived suppressor cells (MDSCs) express TNFR2, and this is directly related to their immunosuppression efficiency. In this article, we investigated the role of the TNFα/TNFR2 immune checkpoint signaling pathway in the immunomodulatory capacities of MSCs. METHODS Co-cultures of MSCs from wild-type (WT) and TNFR2 knocked-out (TNFR2 KO) mice with T cells (WT and TNFα KO) were performed under various experimental conditions. RESULTS We demonstrate that TNFR2 is a key regulatory molecule which is strongly involved in the immunomodulatory properties of MSCs. This includes their ability to suppress T cell proliferation, activation, and pro-inflammatory cytokine production, in addition to their capacity to induce active T regs. CONCLUSIONS Our results reveal for the first time the importance of the TNFα/TNFR2 axis as an active immune checkpoint regulating MSC immunological functions.
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Affiliation(s)
- Ghada Beldi
- INSERM UMR-S-MD 1197, Hôpital Paul Brousse, Villejuif, France.,National Institute of Applied Sciences and Technology (INSAT), Carthage University, LR18ES40, Inflammation, environment and signalization pathologies, Tunis, Tunisia
| | - Maryam Khosravi
- Sorbonne Université, INSERM, CNRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France
| | - Mohamed Essameldin Abdelgawad
- INSERM UMR-S-MD 1197, Hôpital Paul Brousse, Villejuif, France.,Biochemistry Division, Chemistry department, Faculty of Science, Helwan University, Cairo, Egypt
| | - Benoît L Salomon
- Sorbonne Université, INSERM, CNRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France
| | - Georges Uzan
- INSERM UMR-S-MD 1197, Hôpital Paul Brousse, Villejuif, France.,Paris-Saclay University, Villejuif, France
| | - Houda Haouas
- National Institute of Applied Sciences and Technology (INSAT), Carthage University, LR18ES40, Inflammation, environment and signalization pathologies, Tunis, Tunisia.
| | - Sina Naserian
- INSERM UMR-S-MD 1197, Hôpital Paul Brousse, Villejuif, France. .,Paris-Saclay University, Villejuif, France. .,CellMedEx, Saint Maur Des Fossés, France.
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Naserian S, Abdelgawad ME, Afshar Bakshloo M, Ha G, Arouche N, Cohen JL, Salomon BL, Uzan G. The TNF/TNFR2 signaling pathway is a key regulatory factor in endothelial progenitor cell immunosuppressive effect. Cell Commun Signal 2020; 18:94. [PMID: 32546175 PMCID: PMC7298859 DOI: 10.1186/s12964-020-00564-3] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 03/23/2020] [Indexed: 12/13/2022] Open
Abstract
Background Endothelial progenitor cells (EPCs) are non-differentiated endothelial cells (ECs) present in blood circulation that are involved in neo-vascularization and correction of damaged endothelial sites. Since EPCs from patients with vascular disorders are impaired and inefficient, allogenic sources from adult or cord blood are considered as good alternatives. However, due to the reaction of immune system against allogenic cells which usually lead to their elimination, we focused on the exact role of EPCs on immune cells, particularly, T cells which are the most important cells applied in immune rejection. TNFα is one of the main activators of EPCs that recognizes two distinct receptors. TNFR1 is expressed ubiquitously and its interaction with TNFα leads to differentiation and apoptosis, whereas, TNFR2 is expressed predominantly on ECs, immune cells and neural cells and is involved in cell survival and proliferation. Interestingly, it has been shown that different immunosuppressive cells express TNFR2 and this is directly related to their immunosuppressive efficiency. However, little is known about immunological profile and function of TNFR2 in EPCs. Methods Using different in-vitro combinations, we performed co-cultures of ECs and T cells to investigate the immunological effect of EPCs on T cells. We interrupted in the TNFα/TNFR2 axis either by blocking the receptor using TNFR2 antagonist or blocking the ligand using T cells derived from TNFα KO mice. Results We demonstrated that EPCs are able to suppress T cell proliferation and modulate them towards less pro-inflammatory and active phenotypes. Moreover, we showed that TNFα/TNFR2 immune-checkpoint pathway is critical in EPC immunomodulatory effect. Conclusions Our results reveal for the first time a mechanism that EPCs use to suppress immune cells, therefore, enabling them to form new immunosuppressive vessels. Furthermore, we have shown the importance of TNFα/TNFR2 axis in EPCs as an immune checkpoint pathway. We believe that targeting TNFR2 is especially crucial in cancer immune therapy since it controls two crucial aspects of tumor microenvironment: 1) Immunosuppression and 2) Angiogenesis.
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