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Tran Ngoc Minh T, Verleng LJ, Schrama E, Busselaar J, Staal MD, de Vries E, Anholts JDH, Berkers CR, Borst J, Zaal EA, de Kivit S. CD27 costimulation supports metabolic fitness of CD4+ T cells by enhancing de novo nucleotide and protein synthesis. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2025:vkaf075. [PMID: 40324771 DOI: 10.1093/jimmun/vkaf075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Accepted: 03/06/2025] [Indexed: 05/07/2025]
Abstract
T cells undergo many metabolic changes throughout the different phases of their response in lymphoid and nonlymphoid tissues. Cell metabolism meets demands for energy and biosynthesis, particularly during cell division and effector differentiation. As costimulatory receptors, CD28 and various TNF receptor (TNFR) family members shape T-cell clonal expansion, survival and effector functions and are important clinical targets. While CD28 is acknowledged as a metabolic regulator, little is known about how TNFRs shape T-cell metabolism. We here identify TNFR family member CD27 as a metabolic regulator in activated human CD4+ T cells. In the context of CD3 signaling and CD28 costimulation, CD27 proved to regulate specific metabolic functions, as determined by metabolomics and metabolic tracer experiments. CD27 costimulation supported upregulation of glycolysis, the pentose phosphate pathway and the TCA cycle, increasing the use of glucose-derived carbon and glutamine-derived nitrogen as building blocks for de novo nucleotide synthesis. It also promoted uptake of amino acids (AAs) and modulated pathways of AA metabolism. Accordingly, CD27 costimulation boosted protein translation in CD3- and CD3/CD28-activated CD4+ T cells, which proceeded via enhanced mTOR pathway activation. Remarkably, CD27, OX40 and 4-1BB all enhanced CD3-induced mTOR signaling, but only CD27 could overrule inhibitory PD-1 signaling. CD27 costimulation increased IL-2, IFNγ and TNFα production by CD3-activated CD4+ T cells, also in presence of PD-1 signaling. Next to previously defined beneficial effects of CD27 on activated T-cell survival and CTL differentiation and Th1 effector differentiation, these data support its essential contribution to T-cell metabolism and its relevance as a therapeutic target.
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Affiliation(s)
- Thi Tran Ngoc Minh
- Division Cell Biology, Metabolism & Cancer, Department Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands
| | - Lotte J Verleng
- Department of Immunology and Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands
| | - Ellen Schrama
- Department of Immunology and Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands
| | - Julia Busselaar
- Department of Immunology and Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands
| | - Mo D Staal
- Department of Immunology and Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands
| | - Evert de Vries
- Department of Immunology and Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands
| | - Jacqueline D H Anholts
- Department of Immunology and Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands
| | - Celia R Berkers
- Division Cell Biology, Metabolism & Cancer, Department Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands
| | - Jannie Borst
- Department of Immunology and Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands
| | - Esther A Zaal
- Division Cell Biology, Metabolism & Cancer, Department Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands
| | - Sander de Kivit
- Department of Immunology and Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands
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Ma M, Zhang Y, Pu K, Tang W. Nanomaterial-enabled metabolic reprogramming strategies for boosting antitumor immunity. Chem Soc Rev 2025; 54:653-714. [PMID: 39620588 DOI: 10.1039/d4cs00679h] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2025]
Abstract
Immunotherapy has become a crucial strategy in cancer treatment, but its effectiveness is often constrained. Most cancer immunotherapies focus on stimulating T-cell-mediated immunity by driving the cancer-immunity cycle, which includes tumor antigen release, antigen presentation, T cell activation, infiltration, and tumor cell killing. However, metabolism reprogramming in the tumor microenvironment (TME) supports the viability of cancer cells and inhibits the function of immune cells within this cycle, presenting clinical challenges. The distinct metabolic needs of tumor cells and immune cells require precise and selective metabolic interventions to maximize therapeutic outcomes while minimizing adverse effects. Recent advances in nanotherapeutics offer a promising approach to target tumor metabolism reprogramming and enhance the cancer-immunity cycle through tailored metabolic modulation. In this review, we explore cutting-edge nanomaterial strategies for modulating tumor metabolism to improve therapeutic outcomes. We review the design principles of nanoplatforms for immunometabolic modulation, key metabolic pathways and their regulation, recent advances in targeting these pathways for the cancer-immunity cycle enhancement, and future prospects for next-generation metabolic nanomodulators in cancer immunotherapy. We expect that emerging immunometabolic modulatory nanotechnology will establish a new frontier in cancer immunotherapy in the near future.
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Affiliation(s)
- Muye Ma
- Department of Diagnostic Radiology, Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore, 117597, Singapore.
| | - Yongliang Zhang
- Department of Microbiology and Immunology, Immunology Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Dr 2, Singapore, 117545, Singapore
- Immunology Programme, Life Sciences Institute, National University of Singapore, 28 Medical Dr, Singapore, 117597, Singapore
| | - Kanyi Pu
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, 70 Nanyang Drive, Singapore, 637457, Singapore.
- Lee Kong Chian School of Medicine, Nanyang Technological University, 59 Nanyang Drive, Singapore, 636921, Singapore
| | - Wei Tang
- Department of Diagnostic Radiology, Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore, 117597, Singapore.
- Department of Pharmacy and Pharmaceutic Sciences, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore, 117543, Singapore
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Tao Z, Chyra Z, Kotulová J, Celichowski P, Mihályová J, Charvátová S, Hájek R. Impact of T cell characteristics on CAR-T cell therapy in hematological malignancies. Blood Cancer J 2024; 14:213. [PMID: 39627220 PMCID: PMC11615218 DOI: 10.1038/s41408-024-01193-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 11/12/2024] [Accepted: 11/19/2024] [Indexed: 12/06/2024] Open
Abstract
Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment paradigms for hematological malignancies. However, more than half of these patients cannot achieve sustainable tumor control, partially due to the inadequate potency of CAR-T cells in eradicating tumor cells. T cells are crucial components of the anti-tumor immune response, and multiple intrinsic T-cell features significantly influence the outcomes of CAR-T cell therapy. Herein, we review progressing research on T-cell characteristics that impact the effectiveness of CAR-T cells, including T-cell exhaustion, memory subsets, senescence, regulatory T-cells, the CD4+ to CD8+ T-cell ratio, metabolism, and the T-cell receptor repertoire. With comprehensive insight into the biological processes underlying successful CAR-T cell therapy, we will further refine the applications of these novel therapeutic modalities, and enhance their efficacy and safety for patients.
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Affiliation(s)
- Zhongfei Tao
- Department of Haematooncology, University Hospital Ostrava, Ostrava, Czech Republic
- Department of Haematooncology, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
| | - Zuzana Chyra
- Department of Haematooncology, University Hospital Ostrava, Ostrava, Czech Republic
- Department of Haematooncology, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
| | - Jana Kotulová
- Department of Haematooncology, University Hospital Ostrava, Ostrava, Czech Republic
- Department of Haematooncology, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
| | - Piotr Celichowski
- Department of Haematooncology, University Hospital Ostrava, Ostrava, Czech Republic
- Department of Haematooncology, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
| | - Jana Mihályová
- Department of Haematooncology, University Hospital Ostrava, Ostrava, Czech Republic
- Department of Haematooncology, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
| | - Sandra Charvátová
- Department of Haematooncology, University Hospital Ostrava, Ostrava, Czech Republic
- Department of Haematooncology, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
| | - Roman Hájek
- Department of Haematooncology, University Hospital Ostrava, Ostrava, Czech Republic.
- Department of Haematooncology, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic.
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Braverman EL, Qin M, Schuler H, Brown H, Wittmann C, Ramgopal A, Kemp F, Mullet SJ, Yang A, Poholek AC, Gelhaus SL, Byersdorfer CA. AMPK agonism optimizes the in vivo persistence and anti-leukemia efficacy of chimeric antigen receptor T cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.26.615290. [PMID: 39386600 PMCID: PMC11463370 DOI: 10.1101/2024.09.26.615290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 10/12/2024]
Abstract
BACKGROUND Chimeric antigen receptor T cell (CART) therapy has seen great clinical success. However, up to 50% of leukemia patients relapse and long-term survivor data indicate that CART cell persistence is key to enforcing relapse-free survival. Unfortunately, ex vivo expansion protocols often drive metabolic and functional exhaustion, reducing in vivo efficacy. Preclinical models have demonstrated that redirecting metabolism ex vivo can improve in vivo T cell function and we hypothesized that exposure to an agonist targeting the metabolic regulator AMP-activated protein kinase (AMPK), would create CARTs capable of both efficient leukemia clearance and increased in vivo persistence. METHODS CART cells were generated from healthy human via lentiviral transduction. Following activation, cells were exposed to either Compound 991 or DMSO for 96 hours, followed by a 48-hour washout. During and after agonist treatment, T cells were harvested for metabolic and functional assessments. To test in vivo efficacy, immunodeficient mice were injected with luciferase+ NALM6 leukemia cells, followed one week later by either 991- or DMSO-expanded CARTs. Leukemia burden and anti-leukemia efficacy was assessed via radiance imaging and overall survival. RESULTS Human T cells expanded in Compound 991 activated AMPK without limiting cellular expansion and gained both mitochondrial density and improved handling of reactive oxygen species (ROS). Importantly, receipt of 991-exposed CARTs significantly improved in vivo leukemia clearance, prolonged recipient survival, and increased CD4+ T cell yields at early times post-injection. Ex vivo, 991 agonist treatment mimicked nutrient starvation, increased autophagic flux, and promoted generation of mitochondrially-protective metabolites. DISCUSSION Ex vivo expansion processes are necessary to generate sufficient cell numbers, but often promote sustained activation and differentiation, negatively impacting in vivo persistence and function. Here, we demonstrate that promoting AMPK activity during CART expansion metabolically reprograms cells without limiting T cell yield, enhances in vivo anti-leukemia efficacy, and improves CD4+ in vivo persistence. Importantly, AMPK agonism achieves these results without further modifying the expansion media, changing the CART construct, or genetically altering the cells. Altogether, these data highlight AMPK agonism as a potent and readily translatable approach to improve the metabolic profile and overall efficacy of cancer-targeting T cells.
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Affiliation(s)
- Erica L Braverman
- Department of Pediatrics, Division of Blood and Marrow Transplant and Cellular Therapies, University of Pittsburgh School of Medicine, Pittsburgh PA 15224
| | - Mengtao Qin
- Department of Pediatrics, Division of Blood and Marrow Transplant and Cellular Therapies, University of Pittsburgh School of Medicine, Pittsburgh PA 15224
- School of Medicine, Tsinghua University, Beijing, China
| | - Herbert Schuler
- Department of Pediatrics, Division of Blood and Marrow Transplant and Cellular Therapies, University of Pittsburgh School of Medicine, Pittsburgh PA 15224
| | - Harrison Brown
- Department of Pediatrics, Division of Blood and Marrow Transplant and Cellular Therapies, University of Pittsburgh School of Medicine, Pittsburgh PA 15224
| | - Christopher Wittmann
- Department of Pediatrics, Division of Blood and Marrow Transplant and Cellular Therapies, University of Pittsburgh School of Medicine, Pittsburgh PA 15224
| | - Archana Ramgopal
- Department of Pediatrics, Division of Blood and Marrow Transplant and Cellular Therapies, University of Pittsburgh School of Medicine, Pittsburgh PA 15224
| | - Felicia Kemp
- Department of Pediatrics, Division of Blood and Marrow Transplant and Cellular Therapies, University of Pittsburgh School of Medicine, Pittsburgh PA 15224
| | - Steven J Mullet
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States; Health Sciences Mass Spectrometry Core, University of Pittsburgh, Pittsburgh, PA, USA
| | - Aaron Yang
- Department of Pediatrics, Division of Pediatric Rheumatology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Amanda C Poholek
- Department of Pediatrics, Division of Pediatric Rheumatology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Stacy L Gelhaus
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States; Health Sciences Mass Spectrometry Core, University of Pittsburgh, Pittsburgh, PA, USA
| | - Craig A. Byersdorfer
- Department of Pediatrics, Division of Blood and Marrow Transplant and Cellular Therapies, University of Pittsburgh School of Medicine, Pittsburgh PA 15224
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Zhao W, Yao Y, Li Q, Xue Y, Gao X, Liu X, Zhang Q, Zheng J, Sun S. Molecular mechanism of co-stimulatory domains in promoting CAR-T cell anti-tumor efficacy. Biochem Pharmacol 2024; 227:116439. [PMID: 39032532 DOI: 10.1016/j.bcp.2024.116439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 06/28/2024] [Accepted: 07/16/2024] [Indexed: 07/23/2024]
Abstract
Chimeric antigen receptor (CAR)-engineered T cells have been defined as 'living drug'. Adding a co-stimulatory domain (CSD) has enhanced the anti-hematological effects of CAR-T cells, thereby elevating their viability for medicinal applications. Various CSDs have helped prepare CAR-T cells to study anti-tumor efficacy. Previous studies have described and summarized the anti-tumor efficacy of CAR-T cells obtained from different CSDs. However, the underlying molecular mechanisms by which different CSDs affect CAR-T function have been rarely reported. The role of CSDs in T cells has been significantly studied, but whether they can play a unique role as a part of the CAR structure remains undetermined. Here, we summarized the effects of CSDs on CAR-T signaling pathways based on the limited references and speculated the possible mechanism depending on the specific characteristics of CAR-T cells. This review will help understand the molecular mechanism of CSDs in CAR-T cells that exert different anti-tumor effects while providing potential guidance for further interventions to enhance anti-tumor efficacy in immunotherapy.
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Affiliation(s)
- Wanxin Zhao
- Cancer Institute, the First Clinical Medical College, Xuzhou Medical University, Xuzhou, Jiangsu, China; Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Yizhou Yao
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Qihong Li
- Cancer Institute, the First Clinical Medical College, Xuzhou Medical University, Xuzhou, Jiangsu, China; Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Ying Xue
- Cancer Institute, the First Clinical Medical College, Xuzhou Medical University, Xuzhou, Jiangsu, China; Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Xiaoge Gao
- Cancer Institute, the First Clinical Medical College, Xuzhou Medical University, Xuzhou, Jiangsu, China; Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Xiangye Liu
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Qing Zhang
- Cancer Institute, the First Clinical Medical College, Xuzhou Medical University, Xuzhou, Jiangsu, China; Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China.
| | - Junnian Zheng
- Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China.
| | - Shishuo Sun
- Cancer Institute, the First Clinical Medical College, Xuzhou Medical University, Xuzhou, Jiangsu, China; Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China.
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Ng BD, Rajagopalan A, Kousa AI, Fischman JS, Chen S, Massa A, Elias HK, Manuele D, Galiano M, Lemarquis AL, Boardman AP, DeWolf S, Pierce J, Bogen B, James SE, van den Brink MRM. IL-18-secreting multiantigen targeting CAR T cells eliminate antigen-low myeloma in an immunocompetent mouse model. Blood 2024; 144:171-186. [PMID: 38579288 PMCID: PMC11302468 DOI: 10.1182/blood.2023022293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 03/19/2024] [Accepted: 03/20/2024] [Indexed: 04/07/2024] Open
Abstract
ABSTRACT Multiple myeloma is a plasma cell malignancy that is currently incurable with conventional therapies. Following the success of CD19-targeted chimeric antigen receptor (CAR) T cells in leukemia and lymphoma, CAR T cells targeting B-cell maturation antigen (BCMA) more recently demonstrated impressive activity in relapsed and refractory myeloma patients. However, BCMA-directed therapy can fail due to weak expression of BCMA on myeloma cells, suggesting that novel approaches to better address this antigen-low disease may improve patient outcomes. We hypothesized that engineered secretion of the proinflammatory cytokine interleukin-18 (IL-18) and multiantigen targeting could improve CAR T-cell activity against BCMA-low myeloma. In a syngeneic murine model of myeloma, CAR T cells targeting the myeloma-associated antigens BCMA and B-cell activating factor receptor (BAFF-R) failed to eliminate myeloma when these antigens were weakly expressed, whereas IL-18-secreting CAR T cells targeting these antigens promoted myeloma clearance. IL-18-secreting CAR T cells developed an effector-like T-cell phenotype, promoted interferon-gamma production, reprogrammed the myeloma bone marrow microenvironment through type-I/II interferon signaling, and activated macrophages to mediate antimyeloma activity. Simultaneous targeting of weakly-expressed BCMA and BAFF-R with dual-CAR T cells enhanced T-cell:target-cell avidity, increased overall CAR signal strength, and stimulated antimyeloma activity. Dual-antigen targeting augmented CAR T-cell secretion of engineered IL-18 and facilitated elimination of larger myeloma burdens in vivo. Our results demonstrate that combination of engineered IL-18 secretion and multiantigen targeting can eliminate myeloma with weak antigen expression through distinct mechanisms.
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Affiliation(s)
- Brandon D. Ng
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Pharmacology, Weill Cornell Medicine, New York, NY
| | - Adhithi Rajagopalan
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Anastasia I. Kousa
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY
- City of Hope Comprehensive Cancer Center, Duarte, CA
| | - Jacob S. Fischman
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY
- Immunology Graduate Group, University of Pennsylvania, Philadelphia, PA
| | - Sophia Chen
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Alyssa Massa
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY
- City of Hope Comprehensive Cancer Center, Duarte, CA
| | - Harold K. Elias
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY
- Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
| | - Dylan Manuele
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Cornell Medical College, New York, NY
| | - Michael Galiano
- Molecular Cytology Core, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Andri L. Lemarquis
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Alexander P. Boardman
- Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Susan DeWolf
- Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Jonah Pierce
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Immunology and Microbial Pathogenesis, Weill Cornell Medicine, New York, NY
| | | | - Scott E. James
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY
- Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Marcel R. M. van den Brink
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY
- City of Hope Comprehensive Cancer Center, Duarte, CA
- Department of Immunology and Microbial Pathogenesis, Weill Cornell Medicine, New York, NY
- Department of Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY
- Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY
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Franzese O, Ancona P, Bianchi N, Aguiari G. Apoptosis, a Metabolic "Head-to-Head" between Tumor and T Cells: Implications for Immunotherapy. Cells 2024; 13:924. [PMID: 38891056 PMCID: PMC11171541 DOI: 10.3390/cells13110924] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 05/18/2024] [Accepted: 05/22/2024] [Indexed: 06/20/2024] Open
Abstract
Induction of apoptosis represents a promising therapeutic approach to drive tumor cells to death. However, this poses challenges due to the intricate nature of cancer biology and the mechanisms employed by cancer cells to survive and escape immune surveillance. Furthermore, molecules released from apoptotic cells and phagocytes in the tumor microenvironment (TME) can facilitate cancer progression and immune evasion. Apoptosis is also a pivotal mechanism in modulating the strength and duration of anti-tumor T-cell responses. Combined strategies including molecular targeting of apoptosis, promoting immunogenic cell death, modulating immunosuppressive cells, and affecting energy pathways can potentially overcome resistance and enhance therapeutic outcomes. Thus, an effective approach for targeting apoptosis within the TME should delicately balance the selective induction of apoptosis in tumor cells, while safeguarding survival, metabolic changes, and functionality of T cells targeting crucial molecular pathways involved in T-cell apoptosis regulation. Enhancing the persistence and effectiveness of T cells may bolster a more resilient and enduring anti-tumor immune response, ultimately advancing therapeutic outcomes in cancer treatment. This review delves into the pivotal topics of this multifaceted issue and suggests drugs and druggable targets for possible combined therapies.
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Affiliation(s)
- Ornella Franzese
- Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy;
| | - Pietro Ancona
- Department of Translational Medicine, University of Ferrara, Via Fossato di Mortara 70, 44121 Ferrara, Italy;
| | - Nicoletta Bianchi
- Department of Translational Medicine, University of Ferrara, Via Fossato di Mortara 70, 44121 Ferrara, Italy;
| | - Gianluca Aguiari
- Department of Neuroscience and Rehabilitation, University of Ferrara, Via F. Mortara 74, 44121 Ferrara, Italy;
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Li X, Liang X, Fu W, Luo R, Zhang M, Kou X, Zhang Y, Li Y, Huang D, You Y, Wu Q, Gong C. Reversing cancer immunoediting phases with a tumor-activated and optically reinforced immunoscaffold. Bioact Mater 2024; 35:228-241. [PMID: 38333614 PMCID: PMC10850754 DOI: 10.1016/j.bioactmat.2024.01.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 01/19/2024] [Accepted: 01/30/2024] [Indexed: 02/10/2024] Open
Abstract
In situ vaccine (ISV) is a promising immunotherapeutic tactic due to its complete tumoral antigenic repertoire. However, its efficiency is limited by extrinsic inevitable immunosuppression and intrinsic immunogenicity scarcity. To break this plight, a tumor-activated and optically reinforced immunoscaffold (TURN) is exploited to trigger cancer immunoediting phases regression, thus levering potent systemic antitumor immune responses. Upon response to tumoral reactive oxygen species, TURN will first release RGX-104 to attenuate excessive immunosuppressive cells and cytokines, and thus immunosuppression falls and immunogenicity rises. Subsequently, intermittent laser irradiation-activated photothermal agents (PL) trigger abundant tumor antigens exposure, which causes immunogenicity springs and preliminary infiltration of T cells. Finally, CD137 agonists from TURN further promotes the proliferation, function, and survival of T cells for durable antitumor effects. Therefore, cancer immunoediting phases reverse and systemic antitumor immune responses occur. TURN achieves over 90 % tumor growth inhibition in both primary and secondary tumor lesions, induces potent systemic immune responses, and triggers superior long-term immune memory in vivo. Taken together, TURN provides a prospective sight for ISV from the perspective of immunoediting phases.
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Affiliation(s)
- Xinchao Li
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xiuqi Liang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Wangxian Fu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Rui Luo
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Miaomiao Zhang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xiaorong Kou
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yi Zhang
- Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, 110022, China
| | - Yingjie Li
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Dongxue Huang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yanjie You
- Department of Gastroenterology, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, 750002, China
| | - Qinjie Wu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Changyang Gong
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
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9
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Palmeri JR, Lax BM, Peters JM, Duhamel L, Stinson JA, Santollani L, Lutz EA, Pinney W, Bryson BD, Dane Wittrup K. CD8 + T cell priming that is required for curative intratumorally anchored anti-4-1BB immunotherapy is constrained by Tregs. Nat Commun 2024; 15:1900. [PMID: 38429261 PMCID: PMC10907589 DOI: 10.1038/s41467-024-45625-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Accepted: 01/30/2024] [Indexed: 03/03/2024] Open
Abstract
Although co-stimulation of T cells with agonist antibodies targeting 4-1BB (CD137) improves antitumor immune responses in preclinical studies, clinical success has been limited by on-target, off-tumor activity. Here, we report the development of a tumor-anchored ɑ4-1BB agonist (ɑ4-1BB-LAIR), which consists of a ɑ4-1BB antibody fused to the collagen-binding protein LAIR. While combination treatment with an antitumor antibody (TA99) shows only modest efficacy, simultaneous depletion of CD4+ T cells boosts cure rates to over 90% of mice. Mechanistically, this synergy depends on ɑCD4 eliminating tumor draining lymph node regulatory T cells, resulting in priming and activation of CD8+ T cells which then infiltrate the tumor microenvironment. The cytotoxic program of these newly primed CD8+ T cells is then supported by the combined effect of TA99 and ɑ4-1BB-LAIR. The combination of TA99 and ɑ4-1BB-LAIR with a clinically approved ɑCTLA-4 antibody known for enhancing T cell priming results in equivalent cure rates, which validates the mechanistic principle, while the addition of ɑCTLA-4 also generates robust immunological memory against secondary tumor rechallenge. Thus, our study establishes the proof of principle for a clinically translatable cancer immunotherapy.
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Affiliation(s)
- Joseph R Palmeri
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA
- Department of Chemical Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA
| | - Brianna M Lax
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA
- Department of Chemical Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA
| | - Joshua M Peters
- Department of Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA
| | - Lauren Duhamel
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA
- Department of Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA
| | - Jordan A Stinson
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA
- Department of Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA
| | - Luciano Santollani
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA
- Department of Chemical Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA
| | - Emi A Lutz
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA
- Department of Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA
| | - William Pinney
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA
- Department of Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA
| | - Bryan D Bryson
- Department of Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA
| | - K Dane Wittrup
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA.
- Department of Chemical Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA.
- Department of Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA.
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10
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Sun Y, Liu Y, Li R, Zhang C, Wu M, Zhang X, Xu H, Zeng R, Zeng Y, Liu X. Direct visualization of immune status for tumor-infiltrating lymphocytes by rolling circle amplification. JOURNAL OF BIOPHOTONICS 2024; 17:e202300374. [PMID: 37885324 DOI: 10.1002/jbio.202300374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 10/24/2023] [Accepted: 10/24/2023] [Indexed: 10/28/2023]
Abstract
The immune status of tumor-infiltrating lymphocytes (TILs) is essential for the effectiveness of cancer immunotherapies. However, due to the diversity of immune status in TILs, cellular heterogeneity, and the applicability to the clinic, it is still lacking effective strategies to meet clinical needs. We developed a novel immuno-recognition-induced method based on rolling circle amplification (RCA), namely immunoRCA, to in situ visualize the immune status of TILs in actual clinical samples. This developed immunoRCA method, in which, feature mRNAs were used as the biomarkers for the immune status of TILs, has a low fluorescence background, high sensitivity, and specificity. The immunoRCA was able to efficiently evaluate the immune status of CD8+ T cells regulated by activating or inhibiting factors, track the T cell type and immune status during in vitro expansion, and in situ visualize the number, location, and immune status of TILs in clinical specimens.
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Affiliation(s)
- Yupeng Sun
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, People's Republic of China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, People's Republic of China
| | - Yan Liu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, People's Republic of China
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, People's Republic of China
| | - Rui Li
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, People's Republic of China
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, People's Republic of China
| | - Cuilin Zhang
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, People's Republic of China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, People's Republic of China
| | - Ming Wu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, People's Republic of China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, People's Republic of China
| | - Xiaolong Zhang
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, People's Republic of China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, People's Republic of China
| | - Haipo Xu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, People's Republic of China
| | - Rui Zeng
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, People's Republic of China
| | - Yongyi Zeng
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, People's Republic of China
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, People's Republic of China
| | - Xiaolong Liu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, People's Republic of China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, People's Republic of China
- CAS Key Laboratory of Design and Assembly of Functional Nanostructures, Fujian Institute of Research on the Structure of Matter Chinese Academy of Sciences, Fuzhou, People's Republic of China
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11
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Singh R, Kim YH, Lee SJ, Eom HS, Choi BK. 4-1BB immunotherapy: advances and hurdles. Exp Mol Med 2024; 56:32-39. [PMID: 38172595 PMCID: PMC10834507 DOI: 10.1038/s12276-023-01136-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Revised: 09/22/2023] [Accepted: 10/09/2023] [Indexed: 01/05/2024] Open
Abstract
Since its initial description 35 years ago as an inducible molecule expressed in cytotoxic and helper T cells, 4-1BB has emerged as a crucial receptor in T-cell-mediated immune functions. Numerous studies have demonstrated the involvement of 4-1BB in infection and tumor immunity. However, the clinical development of 4-1BB agonist antibodies has been impeded by the occurrence of strong adverse events, notably hepatotoxicity, even though these antibodies have exhibited tremendous promise in in vivo tumor models. Efforts are currently underway to develop a new generation of agonist antibodies and recombinant proteins with modified effector functions that can harness the potent T-cell modulation properties of 4-1BB while mitigating adverse effects. In this review, we briefly examine the role of 4-1BB in T-cell biology, explore its clinical applications, and discuss future prospects in the field of 4-1BB agonist immunotherapy.
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Affiliation(s)
- Rohit Singh
- Immuno-oncology Branch, Division of Rare and Refractory Cancer, National Cancer Center, Goyang, 10408, Republic of Korea
| | - Young-Ho Kim
- Diagnostics and Therapeutics Technology Branch, Division of Technology Convergence, Research Institute, National Cancer Center, Goyang, 10408, Republic of Korea.
| | - Sang-Jin Lee
- Immuno-oncology Branch, Division of Rare and Refractory Cancer, National Cancer Center, Goyang, 10408, Republic of Korea
| | - Hyeon-Seok Eom
- Hematological Malignancy Center, National Cancer Center, Goyang, 10408, Republic of Korea
| | - Beom K Choi
- Immuno-oncology Branch, Division of Rare and Refractory Cancer, National Cancer Center, Goyang, 10408, Republic of Korea.
- Innobationbio, Co., Ltd., Mapo-gu, Seoul, 03929, Republic of Korea.
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12
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Peña-Asensio J, Calvo-Sánchez H, Miquel J, Sanz-de-Villalobos E, González-Praetorius A, Torralba M, Larrubia JR. IL-15 boosts activated HBV core-specific CD8 + progenitor cells via metabolic rebalancing in persistent HBV infection. iScience 2024; 27:108666. [PMID: 38155778 PMCID: PMC10753074 DOI: 10.1016/j.isci.2023.108666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 10/15/2023] [Accepted: 12/05/2023] [Indexed: 12/30/2023] Open
Abstract
A rebalance between energy supply and demand in HBV-specific-CD8+ activated progenitor (AP) cells could restore the functionality of proliferative progeny (PP) in e-antigen(Ag)-negative chronic hepatitis B (CHBe(-)). We observed that quiescent progenitor (QP [TCF1+/FSClow]) HBVcore-specific-CD8+ cells displayed a memory-like phenotype. Following Ag-encounter, the generated AP [TCF1+/FSChigh] subset maintained the PD1+/CD127+ phenotype and gave rise to proliferative progeny (PP [ TCF1-/FSChigh]). In AP cells, IL-15 compared to IL2 decreased the initial mTORC1 boost, but maintained its activation longer linked to a catabolic profile that correlated with enhanced PP effector abilities. In nucleos(t)ide analogue (NUC)-treated CHBe(-), AP subset showed an anabolic phenotype associated with a dysfunctional PP pool. In CHBe(-) cases with low probability of HBVcore-specific-CD8+ cell on-NUC-treatment restoration, according to a clinical predictive model, IL-15/anti-PD-L1 treatment re-established their reactivity. Therefore, IL-15 could improve AP pool energy balance by decreasing intensity but extending T cell activation and by inducing a more catabolic metabolism.
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Affiliation(s)
- Julia Peña-Asensio
- Department of Biology of Systems, University of Alcalá, 28801 Alcalá de Henares, Madrid, Spain
- Instituto de Investigación Sanitaria de Castilla La-Mancha (IDISCAM), 45071 Toledo, Castilla La-Mancha, Spain
| | - Henar Calvo-Sánchez
- Section of Gastroenterology, Guadalajara University Hospital, 19002 Guadalajara, Castilla La-Mancha, Spain
- Department of Medicine & Medical Specialties, University of Alcalá, 28801 Alcalá de Henares, Madrid, Spain
- Instituto de Investigación Sanitaria de Castilla La-Mancha (IDISCAM), 45071 Toledo, Castilla La-Mancha, Spain
| | - Joaquín Miquel
- Section of Gastroenterology, Guadalajara University Hospital, 19002 Guadalajara, Castilla La-Mancha, Spain
- Instituto de Investigación Sanitaria de Castilla La-Mancha (IDISCAM), 45071 Toledo, Castilla La-Mancha, Spain
| | - Eduardo Sanz-de-Villalobos
- Section of Gastroenterology, Guadalajara University Hospital, 19002 Guadalajara, Castilla La-Mancha, Spain
- Instituto de Investigación Sanitaria de Castilla La-Mancha (IDISCAM), 45071 Toledo, Castilla La-Mancha, Spain
| | - Alejandro González-Praetorius
- Section of Microbiology, Guadalajara University Hospital, 19002 Guadalajara, Castilla La-Mancha, Spain
- Instituto de Investigación Sanitaria de Castilla La-Mancha (IDISCAM), 45071 Toledo, Castilla La-Mancha, Spain
| | - Miguel Torralba
- Service of Internal Medicine, Guadalajara University Hospital, 19002 Guadalajara, Castilla La-Mancha, Spain
- Department of Medicine & Medical Specialties, University of Alcalá, 28801 Alcalá de Henares, Madrid, Spain
- Instituto de Investigación Sanitaria de Castilla La-Mancha (IDISCAM), 45071 Toledo, Castilla La-Mancha, Spain
| | - Juan-Ramón Larrubia
- Section of Gastroenterology, Guadalajara University Hospital, 19002 Guadalajara, Castilla La-Mancha, Spain
- Department of Medicine & Medical Specialties, University of Alcalá, 28801 Alcalá de Henares, Madrid, Spain
- Instituto de Investigación Sanitaria de Castilla La-Mancha (IDISCAM), 45071 Toledo, Castilla La-Mancha, Spain
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13
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Yi M, Li T, Niu M, Mei Q, Zhao B, Chu Q, Dai Z, Wu K. Exploiting innate immunity for cancer immunotherapy. Mol Cancer 2023; 22:187. [PMID: 38008741 PMCID: PMC10680233 DOI: 10.1186/s12943-023-01885-w] [Citation(s) in RCA: 82] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 10/23/2023] [Indexed: 11/28/2023] Open
Abstract
Immunotherapies have revolutionized the treatment paradigms of various types of cancers. However, most of these immunomodulatory strategies focus on harnessing adaptive immunity, mainly by inhibiting immunosuppressive signaling with immune checkpoint blockade, or enhancing immunostimulatory signaling with bispecific T cell engager and chimeric antigen receptor (CAR)-T cell. Although these agents have already achieved great success, only a tiny percentage of patients could benefit from immunotherapies. Actually, immunotherapy efficacy is determined by multiple components in the tumor microenvironment beyond adaptive immunity. Cells from the innate arm of the immune system, such as macrophages, dendritic cells, myeloid-derived suppressor cells, neutrophils, natural killer cells, and unconventional T cells, also participate in cancer immune evasion and surveillance. Considering that the innate arm is the cornerstone of the antitumor immune response, utilizing innate immunity provides potential therapeutic options for cancer control. Up to now, strategies exploiting innate immunity, such as agonists of stimulator of interferon genes, CAR-macrophage or -natural killer cell therapies, metabolic regulators, and novel immune checkpoint blockade, have exhibited potent antitumor activities in preclinical and clinical studies. Here, we summarize the latest insights into the potential roles of innate cells in antitumor immunity and discuss the advances in innate arm-targeted therapeutic strategies.
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Affiliation(s)
- Ming Yi
- Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, People's Republic of China
- Department of Breast Surgery, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, 310000, People's Republic of China
| | - Tianye Li
- Department of Gynecology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310000, People's Republic of China
| | - Mengke Niu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, People's Republic of China
| | - Qi Mei
- Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, People's Republic of China
| | - Bin Zhao
- Department of Breast Surgery, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, 310000, People's Republic of China
| | - Qian Chu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, People's Republic of China.
| | - Zhijun Dai
- Department of Breast Surgery, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, 310000, People's Republic of China.
| | - Kongming Wu
- Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, People's Republic of China.
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, People's Republic of China.
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14
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Wang X, Zhou L, Wang H, Chen W, Jiang L, Ming G, Wang J. Metabolic reprogramming, autophagy, and ferroptosis: Novel arsenals to overcome immunotherapy resistance in gastrointestinal cancer. Cancer Med 2023; 12:20573-20589. [PMID: 37860928 PMCID: PMC10660574 DOI: 10.1002/cam4.6623] [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: 04/19/2023] [Revised: 09/05/2023] [Accepted: 09/29/2023] [Indexed: 10/21/2023] Open
Abstract
BACKGROUND Gastrointestinal cancer poses a serious health threat owing to its high morbidity and mortality. Although immune checkpoint blockade (ICB) therapies have achieved meaningful success in most solid tumors, the improvement in survival in gastrointestinal cancers is modest, owing to sparse immune response and widespread resistance. Metabolic reprogramming, autophagy, and ferroptosis are key regulators of tumor progression. METHODS A literature review was conducted to investigate the role of the metabolic reprogramming, autophagy, and ferroptosis in immunotherapy resistance of gastrointestinal cancer. RESULTS Metabolic reprogramming, autophagy, and ferroptosis play pivotal roles in regulating the survival, differentiation, and function of immune cells within the tumor microenvironment. These processes redefine the nutrient allocation blueprint between cancer cells and immune cells, facilitating tumor immune evasion, which critically impacts the therapeutic efficacy of immunotherapy for gastrointestinal cancers. Additionally, there exists profound crosstalk among metabolic reprogramming, autophagy, and ferroptosis. These interactions are paramount in anti-tumor immunity, further promoting the formation of an immunosuppressive microenvironment and resistance to immunotherapy. CONCLUSIONS Consequently, it is imperative to conduct comprehensive research on the roles of metabolic reprogramming, autophagy, and ferroptosis in the resistance of gastrointestinal tumor immunotherapy. This understanding will illuminate the clinical potential of targeting these pathways and their regulatory mechanisms to overcome immunotherapy resistance in gastrointestinal cancers.
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Affiliation(s)
- Xiangwen Wang
- Department of General SurgeryThe First Hospital of Lanzhou UniversityLanzhouChina
| | - Liwen Zhou
- Department of StomatologyThe First Hospital of Lanzhou UniversityLanzhouChina
| | - Hongpeng Wang
- Department of General SurgeryThe First Hospital of Lanzhou UniversityLanzhouChina
| | - Wei Chen
- Department of General SurgeryThe First Hospital of Lanzhou UniversityLanzhouChina
| | - Lei Jiang
- Department of General SurgeryThe First Hospital of Lanzhou UniversityLanzhouChina
| | - Guangtao Ming
- Department of General SurgeryThe First Hospital of Lanzhou UniversityLanzhouChina
| | - Jun Wang
- Department of General SurgeryThe First Hospital of Lanzhou UniversityLanzhouChina
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15
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Panahi Meymandi AR, Akbari B, Soltantoyeh T, Hadjati J, Klionsky DJ, Badie B, Mirzaei HR. Crosstalk between autophagy and metabolic regulation of (CAR) T cells: therapeutic implications. Front Immunol 2023; 14:1212695. [PMID: 37675121 PMCID: PMC10477670 DOI: 10.3389/fimmu.2023.1212695] [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: 04/26/2023] [Accepted: 08/04/2023] [Indexed: 09/08/2023] Open
Abstract
Despite chimeric antigen receptor (CAR) T cell therapy's extraordinary success in subsets of B-cell lymphoma and leukemia, various barriers restrict its application in solid tumors. This has prompted investigating new approaches for producing CAR T cells with superior therapeutic potential. Emerging insights into the barriers to CAR T cell clinical success indicate that autophagy shapes the immune response via reprogramming cellular metabolism and vice versa. Autophagy, a self-cannibalization process that includes destroying and recycling intracellular components in the lysosome, influences T cell biology, including development, survival, memory formation, and cellular metabolism. In this review, we will emphasize the critical role of autophagy in regulating and rewiring metabolic circuits in CAR T cells, as well as how the metabolic status of CAR T cells and the tumor microenvironment (TME) alter autophagy regulation in CAR T cells to restore functional competence in CAR Ts traversing solid TMEs.
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Affiliation(s)
- Ahmad Reza Panahi Meymandi
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Behnia Akbari
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Tahereh Soltantoyeh
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Jamshid Hadjati
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Daniel J. Klionsky
- Life Sciences Institute and Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI, United States
| | - Behnam Badie
- Division of Neurosurgery, City of Hope Beckman Research Institute, Duarte, California, United States
| | - Hamid Reza Mirzaei
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
- Institute for Immunology and Immune Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
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16
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Hosoya H, Rodriguez-Otero P, Sidana S, Borrello IM. Embracing Myeloma Chimeric Antigen Receptor-T: From Scientific Design to Clinical Impact. Am Soc Clin Oncol Educ Book 2023; 43:e389860. [PMID: 37290016 DOI: 10.1200/edbk_389860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Despite recent advancement of treatment strategies in multiple myeloma (MM), patients with relapsed/refractory MM disease, particularly after triple-class refractoriness, continue to have poor prognosis. Chimeric antigen receptor (CAR-T) cells were developed and applied to improve outcomes in this setting, and two products, idecabtagene vicleucel and ciltacabtagene autoleucel, both targeting B-cell maturation antigen, have been approved by the Food and Drug Administration in the United States and European Medicines Agency in Europe. Both have shown unprecedented clinical outcomes with high response rate and prolonged progression-free survival and overall survival in this patient population with grim prognosis. Currently, further investigations are ongoing for CAR-T targeting different tumor antigens such as G protein-coupled receptor, class C, group 5, member D or with different combinations of intracellular signaling domains, as well as fourth-generation CAR-T with antigen-unrestricted inducible cytokines. Although CAR-T therapies hold hopes and enthusiasm from the myeloma community, several hurdles remain before these treatments become available for all patients in need. These barriers include CAR-T-cell manufacturing availability, access to administering centers, financial cost, caregivers' availability, and socioeconomic and racial disparities. Expanding clinical trial eligibility criteria and real-world data collection and analysis is crucial to understand the efficacy and safety of CAR-T in the patient cohort who tends to be excluded from current trials.
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Affiliation(s)
- Hitomi Hosoya
- Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, CA
| | - Paula Rodriguez-Otero
- Clínica Universidad de Navarra, CCUN, Centro de investigación médica aplicada (Cima), IDISNA, CIBERONC, Pamplona, Spain
| | - Surbhi Sidana
- Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, CA
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17
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Peng JJ, Wang L, Li Z, Ku CL, Ho PC. Metabolic challenges and interventions in CAR T cell therapy. Sci Immunol 2023; 8:eabq3016. [PMID: 37058548 DOI: 10.1126/sciimmunol.abq3016] [Citation(s) in RCA: 55] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/16/2023]
Abstract
Chimeric antigen receptor (CAR) T cells have achieved true clinical success in treating hematological malignancy patients, laying the foundation of CAR T cells as a new pillar of cancer therapy. Although these promising effects have generated strong interest in expanding the treatment of CAR T cells to solid tumors, reproducible demonstration of clinical efficacy in the setting of solid tumors has remained challenging to date. Here, we review how metabolic stress and signaling in the tumor microenvironment, including intrinsic determinants of response to CAR T cell therapy and extrinsic obstacles, restrict the efficacy of CAR T cell therapy in cancer treatment. In addition, we discuss the use of novel approaches to target and rewire metabolic programming for CAR T cell manufacturing. Last, we summarize strategies that aim to improve the metabolic adaptability of CAR T cells to enhance their potency in mounting antitumor responses and survival within the tumor microenvironment.
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Affiliation(s)
- Jhan-Jie Peng
- Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland
- Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland
- Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan
| | - Limei Wang
- Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland
- Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland
| | - Zhiyu Li
- Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland
- Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, P.R. China
| | - Cheng-Lung Ku
- Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan
| | - Ping-Chih Ho
- Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland
- Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland
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18
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Palmeri JR, Lax BM, Peters JM, Duhamel L, Stinson JA, Santollani L, Lutz EA, Pinney W, Bryson BD, Wittrup KD. Tregs constrain CD8 + T cell priming required for curative intratumorally anchored anti-4-1BB immunotherapy. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.30.526116. [PMID: 36778460 PMCID: PMC9915483 DOI: 10.1101/2023.01.30.526116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Although co-stimulation of T cells with agonist antibodies targeting 4-1BB (CD137) improves antitumor immune responses in preclinical studies, clinical development has been hampered by on-target, off-tumor toxicity. Here, we report the development of a tumor-anchored ɑ4-1BB agonist (ɑ4-1BB-LAIR), which consists of an ɑ4-1BB antibody fused to the collagen binding protein LAIR. While combination treatment with an antitumor antibody (TA99) displayed only modest efficacy, simultaneous depletion of CD4+ T cells boosted cure rates to over 90% of mice. We elucidated two mechanisms of action for this synergy: ɑCD4 eliminated tumor draining lymph node Tregs, enhancing priming and activation of CD8+ T cells, and TA99 + ɑ4-1BB-LAIR supported the cytotoxic program of these newly primed CD8+ T cells within the tumor microenvironment. Replacement of ɑCD4 with ɑCTLA-4, a clinically approved antibody that enhances T cell priming, produced equivalent cure rates while additionally generating robust immunological memory against secondary tumor rechallenge.
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Affiliation(s)
- Joseph R Palmeri
- Koch Institute for Integrative Cancer Research; Cambridge, MA
- Department of Chemical Engineering of Massachusetts Institute of Technology (MIT); Cambridge, MA
| | - Brianna M Lax
- Koch Institute for Integrative Cancer Research; Cambridge, MA
- Department of Chemical Engineering of Massachusetts Institute of Technology (MIT); Cambridge, MA
| | - Joshua M Peters
- Department of Biological Engineering of Massachusetts Institute of Technology (MIT); Cambridge, MA
- Ragon Institute of MIT, MGH, and Harvard; Cambridge, MA
| | - Lauren Duhamel
- Koch Institute for Integrative Cancer Research; Cambridge, MA
- Department of Biological Engineering of Massachusetts Institute of Technology (MIT); Cambridge, MA
| | - Jordan A Stinson
- Koch Institute for Integrative Cancer Research; Cambridge, MA
- Department of Biological Engineering of Massachusetts Institute of Technology (MIT); Cambridge, MA
| | - Luciano Santollani
- Koch Institute for Integrative Cancer Research; Cambridge, MA
- Department of Chemical Engineering of Massachusetts Institute of Technology (MIT); Cambridge, MA
| | - Emi A Lutz
- Koch Institute for Integrative Cancer Research; Cambridge, MA
- Department of Biological Engineering of Massachusetts Institute of Technology (MIT); Cambridge, MA
| | - William Pinney
- Koch Institute for Integrative Cancer Research; Cambridge, MA
- Department of Biological Engineering of Massachusetts Institute of Technology (MIT); Cambridge, MA
| | - Bryan D Bryson
- Department of Biological Engineering of Massachusetts Institute of Technology (MIT); Cambridge, MA
- Ragon Institute of MIT, MGH, and Harvard; Cambridge, MA
| | - K Dane Wittrup
- Koch Institute for Integrative Cancer Research; Cambridge, MA
- Department of Chemical Engineering of Massachusetts Institute of Technology (MIT); Cambridge, MA
- Department of Biological Engineering of Massachusetts Institute of Technology (MIT); Cambridge, MA
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19
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Metabolic Regulation of T cell Activity: Implications for Metabolic-Based T-cell Therapies for Cancer. IRANIAN BIOMEDICAL JOURNAL 2023; 27:1-14. [PMID: 36624636 PMCID: PMC9971708 DOI: 10.52547/ibj.3811] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Immunometabolism is an emerging field in tumor immunotherapy. Understanding the metabolic competition for access to the limited nutrients between tumor cells and immune cells can reveal the complexity of the tumor microenvironment and help develop new therapeutic approaches for cancer. Recent studies have focused on modifying the function of immune cells by manipulating their metabolic pathways. Besides, identifying metabolic events, which affect the function of immune cells leads to new therapeutic opportunities for treatment of inflammatory diseases and immune-related conditions. According to the literature, metabolic pathway such as glycolysis, tricarboxylic acid cycle, and fatty acid metabolism, significantly influence the survival, proliferation, activation, and function of immune cells and thus regulate immune responses. In this paper, we reviewed the role of metabolic processes and major signaling pathways involving in T-cell regulation and T-cell responses against tumor cells. Moreover, we summarized the new therapeutics suggested to enhance anti-tumor activity of T cells through manipulating metabolic pathways.
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20
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Claus C, Ferrara-Koller C, Klein C. The emerging landscape of novel 4-1BB (CD137) agonistic drugs for cancer immunotherapy. MAbs 2023; 15:2167189. [PMID: 36727218 PMCID: PMC9897756 DOI: 10.1080/19420862.2023.2167189] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 01/05/2023] [Accepted: 01/06/2023] [Indexed: 02/03/2023] Open
Abstract
The clinical development of 4-1BB agonists for cancer immunotherapy has raised substantial interest during the past decade. The first generation of 4-1BB agonistic antibodies entering the clinic, urelumab (BMS-663513) and utomilumab (PF-05082566), failed due to (liver) toxicity or lack of efficacy, respectively. The two antibodies display differences in the affinity and the 4-1BB receptor epitope recognition, as well as the isotype, which determines the Fc-gamma-receptor (FcγR) crosslinking activity. Based on this experience a very diverse landscape of second-generation 4-1BB agonists addressing the liabilities of first-generation agonists has recently been developed, with many entering clinical Phase 1 and 2 studies. This review provides an overview focusing on differences and their scientific rationale, as well as challenges foreseen during the clinical development of these molecules.
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Affiliation(s)
- Christina Claus
- Roche Innovation Center Zurich, Roche Pharma Research and Early Development (pRED), Schlieren, Switzerland
| | - Claudia Ferrara-Koller
- Roche Innovation Center Zurich, Roche Pharma Research and Early Development (pRED), Schlieren, Switzerland
| | - Christian Klein
- Roche Innovation Center Zurich, Roche Pharma Research and Early Development (pRED), Schlieren, Switzerland
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21
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Chen C, Wang Z, Ding Y, Qin Y. Manipulating T-cell metabolism to enhance immunotherapy in solid tumor. Front Immunol 2022; 13:1090429. [PMID: 36618408 PMCID: PMC9812959 DOI: 10.3389/fimmu.2022.1090429] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Accepted: 11/29/2022] [Indexed: 12/24/2022] Open
Abstract
Cellular metabolism is not only essential for tumor cells to sustain their rapid growth and proliferation, but also crucial to maintain T cell fitness and robust immunity. Dysregulated metabolism has been recognized as a hallmark of cancer, which provides survival advantages for tumor cells under stress conditions. Also, emerging evidence suggests that metabolic reprogramming impacts the activation, differentiation, function, and exhaustion of T cells. Normal stimulation of resting T cells promotes the conversion of catabolic and oxidative metabolism to aerobic glycolysis in effector T cells, and subsequently back to oxidative metabolism in memory T cells. These metabolic transitions profoundly affect the trajectories of T-cell differentiation and fate. However, these metabolic events of T cells could be dysregulated by their interplays with tumor or the tumor microenvironment (TME). Importantly, metabolic competition in the tumor ecosystem is a new mechanism resulting in strong suppression of effector T cells. It is appreciated that targeting metabolic reprogramming is a promising way to disrupt the hypermetabolic state of tumor cells and enhance the capacity of immune cells to obtain nutrients. Furthermore, immunotherapies, such as immune checkpoint inhibitor (ICI), adoptive cell therapy (ACT), and oncolytic virus (OV) therapy, have significantly refashioned the clinical management of solid tumors, they are not sufficiently effective for all patients. Understanding how immunotherapy affects T cell metabolism provides a bright avenue to better modulate T cell anti-tumor response. In this review, we provide an overview of the cellular metabolism of tumor and T cells, provide evidence on their dynamic interaction, highlight how metabolic reprogramming of tumor and T cells regulate the anti-tumor responses, describe T cell metabolic patterns in the context of ICI, ACT, and OV, and propose hypothetical combination strategies to favor potent T cell functionality.
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22
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Abdeladhim M, Karnell JL, Rieder SA. In or out of control: Modulating regulatory T cell homeostasis and function with immune checkpoint pathways. Front Immunol 2022; 13:1033705. [PMID: 36591244 PMCID: PMC9799097 DOI: 10.3389/fimmu.2022.1033705] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 11/16/2022] [Indexed: 12/16/2022] Open
Abstract
Regulatory T cells (Tregs) are the master regulators of immunity and they have been implicated in different disease states such as infection, autoimmunity and cancer. Since their discovery, many studies have focused on understanding Treg development, differentiation, and function. While there are many players in the generation and function of truly suppressive Tregs, the role of checkpoint pathways in these processes have been studied extensively. In this paper, we systematically review the role of different checkpoint pathways in Treg homeostasis and function. We describe how co-stimulatory and co-inhibitory pathways modulate Treg homeostasis and function and highlight data from mouse and human studies. Multiple checkpoint pathways are being targeted in cancer and autoimmunity; therefore, we share insights from the clinic and discuss the effect of experimental and approved therapeutics on Treg biology.
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23
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Li H, Zhao A, Li M, Shi L, Han Q, Hou Z. Targeting T-cell metabolism to boost immune checkpoint inhibitor therapy. Front Immunol 2022; 13:1046755. [PMID: 36569893 PMCID: PMC9768337 DOI: 10.3389/fimmu.2022.1046755] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Accepted: 11/21/2022] [Indexed: 12/12/2022] Open
Abstract
Immune checkpoint inhibitors (ICIs) have shown promising therapeutic effects in the treatment of advanced solid cancers, but their overall response rate is still very low for certain tumor subtypes, limiting their clinical scope. Moreover, the high incidence of drug resistance (including primary and acquired) and adverse effects pose significant challenges to the utilization of these therapies in the clinic. ICIs enhance T cell activation and reverse T cell exhaustion, which is a complex and multifactorial process suggesting that the regulatory mechanisms of ICI therapy are highly heterogeneous. Recently, metabolic reprogramming has emerged as a novel means of reversing T-cell exhaustion in the tumor microenvironment; there is increasing evidence that T cell metabolic disruption limits the therapeutic effect of ICIs. This review focuses on the crosstalk between T-cell metabolic reprogramming and ICI therapeutic efficacy, and summarizes recent strategies to improve drug tolerance and enhance anti-tumor effects by targeting T-cell metabolism alongside ICI therapy. The identification of potential targets for altering T-cell metabolism can significantly contribute to the development of methods to predict therapeutic responsiveness in patients receiving ICI therapy, which are currently unknown but would be of great clinical significance.
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Affiliation(s)
- Haohao Li
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, China
| | - Alison Zhao
- Cleveland Clinic Lerner College of Medicine at Case Western Reserve School of Medicine, Cleveland, OH, United States
| | - Menghua Li
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, China
| | - Lizhi Shi
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, China
| | - Qiuju Han
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, China,*Correspondence: Qiuju Han, ; Zhaohua Hou,
| | - Zhaohua Hou
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States,*Correspondence: Qiuju Han, ; Zhaohua Hou,
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24
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Wang Y, Wang Y, Ren Y, Zhang Q, Yi P, Cheng C. Metabolic modulation of immune checkpoints and novel therapeutic strategies in cancer. Semin Cancer Biol 2022; 86:542-565. [PMID: 35151845 DOI: 10.1016/j.semcancer.2022.02.010] [Citation(s) in RCA: 80] [Impact Index Per Article: 26.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 12/08/2021] [Accepted: 02/05/2022] [Indexed: 02/07/2023]
Abstract
Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) or programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1)-based immune checkpoint inhibitors (ICIs) have led to significant improvements in the overall survival of patients with certain cancers and are expected to benefit patients by achieving complete, long-lasting remissions and cure. However, some patients who receive ICIs either fail treatment or eventually develop immunotherapy resistance. The existence of such patients necessitates a deeper understanding of cancer progression, specifically nutrient regulation in the tumor microenvironment (TME), which includes both metabolic cross-talk between metabolites and tumor cells, and intracellular metabolism in immune and cancer cells. Here we review the features and behaviors of the TME and discuss the recently identified major immune checkpoints. We comprehensively and systematically summarize the metabolic modulation of tumor immunity and immune checkpoints in the TME, including glycolysis, amino acid metabolism, lipid metabolism, and other metabolic pathways, and further discuss the potential metabolism-based therapeutic strategies tested in preclinical and clinical settings. These findings will help to determine the existence of a link or crosstalk between tumor metabolism and immunotherapy, which will provide an important insight into cancer treatment and cancer research.
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Affiliation(s)
- Yi Wang
- Health Management Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China; Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, 610072, China
| | - Yuya Wang
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, 401120, China
| | - Yifei Ren
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, 401120, China; Department of Obstetrics and Gynecology, Daping Hospital, Army Medical Center, Chongqing, 400038, China
| | - Qi Zhang
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610054, China
| | - Ping Yi
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, 401120, China.
| | - Chunming Cheng
- Department of Radiation Oncology, James Comprehensive Cancer Center and College of Medicine at The Ohio State University, Columbus, OH, 43221, United States.
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25
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Zhou Z, Tao C, Li J, Tang JCO, Chan ASC, Zhou Y. Chimeric antigen receptor T cells applied to solid tumors. Front Immunol 2022; 13:984864. [PMID: 36389701 PMCID: PMC9659902 DOI: 10.3389/fimmu.2022.984864] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Accepted: 10/18/2022] [Indexed: 12/02/2022] Open
Abstract
Chimeric antigen receptor T cell (CAR-T) therapy is novel tumor immunotherapy that enables autologous T to express synthetic receptors to specifically recognize the surface tumor-associated antigens for exerting subsequent antitumor effects, and eliminating the resistance, metastases and recurrence of cancer. Although CAR T cells have exhibited success in eradicating hematologic malignancies, their applications to solid tumors has not yet been achieved due to obstacles such as the immune-suppressor tumor microenvironment and lack of tumor specific target antigens. In this review, we presented advancements in the development of CAR T cell therapy in solid tumors, and offered a brief summary of the challenges, as well as novel engineering and pharmaceutical interventions to overcome these barriers. Looking forward, we discussed the latest studies which are expected to reach the clinicals in the next few years, including CRISPR screens-based CAR modification and CAR T cells driven from progenitor-like T cells. Collectively, this review may inspire researchers and clinicians to develop clinical available strategies of CAR T cell therapies in solid tumor.
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Affiliation(s)
- Zhongguo Zhou
- School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia
- School of Biomedical Engineering, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Can Tao
- School of Clinical Medicine, Anhui Medical University, Hefei, Anhui, China
| | - Jianting Li
- School of Biomedical Engineering, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Johnny Cheuk-on Tang
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, Hong Kong SAR, China
- Kamford Genetics Company Limited, Hong Kong, Hong Kong SAR, China
| | - Albert Sun-chi Chan
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yuanyuan Zhou
- School of Biomedical Engineering, Sun Yat-sen University, Guangzhou, Guangdong, China
- *Correspondence: Yuanyuan Zhou,
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26
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Ping Y, Shen C, Huang B, Zhang Y. Reprogramming T-Cell Metabolism for Better Anti-Tumor Immunity. Cells 2022; 11:3103. [PMID: 36231064 PMCID: PMC9562038 DOI: 10.3390/cells11193103] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 09/09/2022] [Accepted: 09/28/2022] [Indexed: 11/17/2022] Open
Abstract
T cells play central roles in the anti-tumor immunity, whose activation and differentiation are profoundly regulated by intrinsic metabolic reprogramming. Emerging evidence has revealed that metabolic processes of T cells are generally altered by tumor cells or tumor released factors, leading to crippled anti-tumor immunity. Therefore, better understanding of T cell metabolic mechanism is crucial in developing the next generation of T cell-based anti-tumor immunotherapeutics. In this review, we discuss how metabolic pathways affect T cells to exert their anti-tumor effects and how to remodel the metabolic programs to improve T cell-mediated anti-tumor immune responses. We emphasize that glycolysis, carboxylic acid cycle, fatty acid oxidation, cholesterol metabolism, amino acid metabolism, and nucleotide metabolism work together to tune tumor-reactive T-cell activation and proliferation.
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Affiliation(s)
- Yu Ping
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Chunyi Shen
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Bo Huang
- Department of Immunology & National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College, Beijing 100005, China
| | - Yi Zhang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
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27
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Xiao C, Tian H, Zheng Y, Yang Z, Li S, Fan T, Xu J, Bai G, Liu J, Deng Z, Li C, He J. Glycolysis in tumor microenvironment as a target to improve cancer immunotherapy. Front Cell Dev Biol 2022; 10:1013885. [PMID: 36200045 PMCID: PMC9527271 DOI: 10.3389/fcell.2022.1013885] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 09/07/2022] [Indexed: 12/03/2022] Open
Abstract
Cancer cells and immune cells all undergo remarkably metabolic reprogramming during the oncogenesis and tumor immunogenic killing processes. The increased dependency on glycolysis is the most typical trait, profoundly involved in the tumor immune microenvironment and cancer immunity regulation. However, how to best utilize glycolytic targets to boost anti-tumor immunity and improve immunotherapies are not fully illustrated. In this review, we describe the glycolytic remodeling of various immune cells within the tumor microenvironment (TME) and the deleterious effects of limited nutrients and acidification derived from enhanced tumor glycolysis on immunological anti-tumor capacity. Moreover, we elucidate the underlying regulatory mechanisms of glycolytic reprogramming, including the crosstalk between metabolic pathways and immune checkpoint signaling. Importantly, we summarize the potential glycolysis-related targets that are expected to improve immunotherapy benefits. Our understanding of metabolic effects on anti-tumor immunity will be instrumental for future therapeutic regimen development.
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Affiliation(s)
- Chu Xiao
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - He Tian
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Yujia Zheng
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Zhenlin Yang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Shuofeng Li
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Tao Fan
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Jiachen Xu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Guangyu Bai
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Jingjing Liu
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Ziqin Deng
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Chunxiang Li
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
- *Correspondence: Chunxiang Li, ; Jie He,
| | - Jie He
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
- *Correspondence: Chunxiang Li, ; Jie He,
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28
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Sainero-Alcolado L, Liaño-Pons J, Ruiz-Pérez MV, Arsenian-Henriksson M. Targeting mitochondrial metabolism for precision medicine in cancer. Cell Death Differ 2022; 29:1304-1317. [PMID: 35831624 PMCID: PMC9287557 DOI: 10.1038/s41418-022-01022-y] [Citation(s) in RCA: 171] [Impact Index Per Article: 57.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 05/16/2022] [Accepted: 05/16/2022] [Indexed: 12/13/2022] Open
Abstract
During decades, the research field of cancer metabolism was based on the Warburg effect, described almost one century ago. Lately, the key role of mitochondria in cancer development has been demonstrated. Many mitochondrial pathways including oxidative phosphorylation, fatty acid, glutamine, and one carbon metabolism are altered in tumors, due to mutations in oncogenes and tumor suppressor genes, as well as in metabolic enzymes. This results in metabolic reprogramming that sustains rapid cell proliferation and can lead to an increase in reactive oxygen species used by cancer cells to maintain pro-tumorigenic signaling pathways while avoiding cellular death. The knowledge acquired on the importance of mitochondrial cancer metabolism is now being translated into clinical practice. Detailed genomic, transcriptomic, and metabolomic analysis of tumors are necessary to develop more precise treatments. The successful use of drugs targeting metabolic mitochondrial enzymes has highlighted the potential for their use in precision medicine and many therapeutic candidates are in clinical trials. However, development of efficient personalized drugs has proved challenging and the combination with other strategies such as chemocytotoxic drugs, immunotherapy, and ketogenic or calorie restriction diets is likely necessary to boost their potential. In this review, we summarize the main mitochondrial features, metabolic pathways, and their alterations in different cancer types. We also present an overview of current inhibitors, highlight enzymes that are attractive targets, and discuss challenges with translation of these approaches into clinical practice. The role of mitochondria in cancer is indisputable and presents several attractive targets for both tailored and personalized cancer therapy. ![]()
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Affiliation(s)
- Lourdes Sainero-Alcolado
- Department of Microbiology, Tumor and Cell Biology (MTC), Biomedicum B7, Karolinska Institutet, SE-171 65, Stockholm, Sweden
| | - Judit Liaño-Pons
- Department of Microbiology, Tumor and Cell Biology (MTC), Biomedicum B7, Karolinska Institutet, SE-171 65, Stockholm, Sweden
| | - María Victoria Ruiz-Pérez
- Department of Microbiology, Tumor and Cell Biology (MTC), Biomedicum B7, Karolinska Institutet, SE-171 65, Stockholm, Sweden
| | - Marie Arsenian-Henriksson
- Department of Microbiology, Tumor and Cell Biology (MTC), Biomedicum B7, Karolinska Institutet, SE-171 65, Stockholm, Sweden.
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29
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Forcados C, Joaquina S, Casey NP, Caulier B, Wälchli S. How CAR T Cells Breathe. Cells 2022; 11:cells11091454. [PMID: 35563759 PMCID: PMC9102061 DOI: 10.3390/cells11091454] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 04/19/2022] [Accepted: 04/22/2022] [Indexed: 02/06/2023] Open
Abstract
The manufacture of efficacious CAR T cells represents a major challenge in cellular therapy. An important aspect of their quality concerns energy production and consumption, known as metabolism. T cells tend to adopt diverse metabolic profiles depending on their differentiation state and their stimulation level. It is therefore expected that the introduction of a synthetic molecule such as CAR, activating endogenous signaling pathways, will affect metabolism. In addition, upon patient treatment, the tumor microenvironment might influence the CAR T cell metabolism by compromising the energy resources. The access to novel technology with higher throughput and reduced cost has led to an increased interest in studying metabolism. Indeed, methods to quantify glycolysis and mitochondrial respiration have been available for decades but were rarely applied in the context of CAR T cell therapy before the release of the Seahorse XF apparatus. The present review will focus on the use of this instrument in the context of studies describing the impact of CAR on T cell metabolism and the strategies to render of CAR T cells more metabolically fit.
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Affiliation(s)
- Christopher Forcados
- Translational Research Unit, Department of Cellular Therapy, Oslo University Hospital, 0379 Oslo, Norway; (C.F.); (S.J.); (N.P.C.); (B.C.)
| | - Sandy Joaquina
- Translational Research Unit, Department of Cellular Therapy, Oslo University Hospital, 0379 Oslo, Norway; (C.F.); (S.J.); (N.P.C.); (B.C.)
| | - Nicholas Paul Casey
- Translational Research Unit, Department of Cellular Therapy, Oslo University Hospital, 0379 Oslo, Norway; (C.F.); (S.J.); (N.P.C.); (B.C.)
| | - Benjamin Caulier
- Translational Research Unit, Department of Cellular Therapy, Oslo University Hospital, 0379 Oslo, Norway; (C.F.); (S.J.); (N.P.C.); (B.C.)
- Center for Cancer Cell Reprogramming (CanCell), Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, 0372 Oslo, Norway
- Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, 0379 Oslo, Norway
| | - Sébastien Wälchli
- Translational Research Unit, Department of Cellular Therapy, Oslo University Hospital, 0379 Oslo, Norway; (C.F.); (S.J.); (N.P.C.); (B.C.)
- Correspondence:
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30
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Understanding of Immune Escape Mechanisms and Advances in Cancer Immunotherapy. JOURNAL OF ONCOLOGY 2022; 2022:8901326. [PMID: 35401745 PMCID: PMC8989557 DOI: 10.1155/2022/8901326] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/15/2022] [Accepted: 03/16/2022] [Indexed: 12/21/2022]
Abstract
Tumor immune escape has emerged as the most significant barrier to cancer therapy. A thorough understanding of tumor immune escape therapy mechanisms is critical for further improving clinical treatment strategies. Currently, research indicates that combining several immunotherapies can boost antitumor efficacy and encourage T cells to play a more active part in the immune assault. To generate a more substantial therapeutic impact, it can establish an ideal tumor microenvironment (TME), encourage T cells to play a role, prevent T cell immune function reversal, and minimize tumor immune tolerance. In this review, we will examine the mechanisms of tumor immune escape and the limits of tumor immune escape therapy, focusing on the current development of immunotherapy based on tumor immune escape mechanisms. Individualized tumor treatment is becoming increasingly apparent as future treatment strategies. In addition, we forecast the future research direction of cancer and the clinical approach for cancer immunotherapy. It will serve as a better reference for researchers working in cancer therapy research.
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31
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Yuan Y, Li H, Pu W, Chen L, Guo D, Jiang H, He B, Qin S, Wang K, Li N, Feng J, Wen J, Cheng S, Zhang Y, Yang W, Ye D, Lu Z, Huang C, Mei J, Zhang HF, Gao P, Jiang P, Su S, Sun B, Zhao SM. Cancer metabolism and tumor microenvironment: fostering each other? SCIENCE CHINA. LIFE SCIENCES 2022; 65:236-279. [PMID: 34846643 DOI: 10.1007/s11427-021-1999-2] [Citation(s) in RCA: 88] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Accepted: 08/19/2021] [Indexed: 02/06/2023]
Abstract
The changes associated with malignancy are not only in cancer cells but also in environment in which cancer cells live. Metabolic reprogramming supports tumor cell high demand of biogenesis for their rapid proliferation, and helps tumor cell to survive under certain genetic or environmental stresses. Emerging evidence suggests that metabolic alteration is ultimately and tightly associated with genetic changes, in particular the dysregulation of key oncogenic and tumor suppressive signaling pathways. Cancer cells activate HIF signaling even in the presence of oxygen and in the absence of growth factor stimulation. This cancer metabolic phenotype, described firstly by German physiologist Otto Warburg, insures enhanced glycolytic metabolism for the biosynthesis of macromolecules. The conception of metabolite signaling, i.e., metabolites are regulators of cell signaling, provides novel insights into how reactive oxygen species (ROS) and other metabolites deregulation may regulate redox homeostasis, epigenetics, and proliferation of cancer cells. Moreover, the unveiling of noncanonical functions of metabolic enzymes, such as the moonlighting functions of phosphoglycerate kinase 1 (PGK1), reassures the importance of metabolism in cancer development. The metabolic, microRNAs, and ncRNAs alterations in cancer cells can be sorted and delivered either to intercellular matrix or to cancer adjacent cells to shape cancer microenvironment via media such as exosome. Among them, cancer microenvironmental cells are immune cells which exert profound effects on cancer cells. Understanding of all these processes is a prerequisite for the development of a more effective strategy to contain cancers.
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Affiliation(s)
- Yiyuan Yuan
- Obstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200438, China
| | - Huimin Li
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Wang Pu
- Molecular and Cell Biology Lab, Institutes of Biomedical Sciences and School of Life Sciences, Fudan University, Shanghai, 200032, China
| | - Leilei Chen
- Molecular and Cell Biology Lab, Institutes of Biomedical Sciences and School of Life Sciences, Fudan University, Shanghai, 200032, China
| | - Dong Guo
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310029, China
| | - Hongfei Jiang
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310029, China
| | - Bo He
- West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Siyuan Qin
- West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Kui Wang
- West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Na Li
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Jingwei Feng
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Jing Wen
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China.,School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
| | - Shipeng Cheng
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China.,School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
| | - Yaguang Zhang
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China.,School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
| | - Weiwei Yang
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China.
| | - Dan Ye
- Molecular and Cell Biology Lab, Institutes of Biomedical Sciences and School of Life Sciences, Fudan University, Shanghai, 200032, China.
| | - Zhimin Lu
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310029, China.
| | - Canhua Huang
- West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China.
| | - Jun Mei
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| | - Hua-Feng Zhang
- CAS Centre for Excellence in Cell and Molecular Biology, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China.
| | - Ping Gao
- School of Medicine, Institutes for Life Sciences, South China University of Technology, Guangzhou, 510006, China.
| | - Peng Jiang
- Tsinghua University School of Life Sciences, and Tsinghua-Peking Center for Life Sciences, Beijing, 100084, China.
| | - Shicheng Su
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
| | - Bing Sun
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China. .,School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
| | - Shi-Min Zhao
- Obstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200438, China.
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32
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Stirling ER, Bronson SM, Mackert JD, Cook KL, Triozzi PL, Soto-Pantoja DR. Metabolic Implications of Immune Checkpoint Proteins in Cancer. Cells 2022; 11:179. [PMID: 35011741 PMCID: PMC8750774 DOI: 10.3390/cells11010179] [Citation(s) in RCA: 21] [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: 10/27/2021] [Revised: 12/20/2021] [Accepted: 12/29/2021] [Indexed: 12/29/2022] Open
Abstract
Expression of immune checkpoint proteins restrict immunosurveillance in the tumor microenvironment; thus, FDA-approved checkpoint inhibitor drugs, specifically PD-1/PD-L1 and CTLA-4 inhibitors, promote a cytotoxic antitumor immune response. Aside from inflammatory signaling, immune checkpoint proteins invoke metabolic reprogramming that affects immune cell function, autonomous cancer cell bioenergetics, and patient response. Therefore, this review will focus on the metabolic alterations in immune and cancer cells regulated by currently approved immune checkpoint target proteins and the effect of costimulatory receptor signaling on immunometabolism. Additionally, we explore how diet and the microbiome impact immune checkpoint blockade therapy response. The metabolic reprogramming caused by targeting these proteins is essential in understanding immune-related adverse events and therapeutic resistance. This can provide valuable information for potential biomarkers or combination therapy strategies targeting metabolic pathways with immune checkpoint blockade to enhance patient response.
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Affiliation(s)
- Elizabeth R. Stirling
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; (E.R.S.); (K.L.C.); (P.L.T.)
| | - Steven M. Bronson
- Department of Pathology, Section of Comparative Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA;
- Department of Internal Medicine, Section of Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
| | - Jessica D. Mackert
- Department of Surgery, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA;
| | - Katherine L. Cook
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; (E.R.S.); (K.L.C.); (P.L.T.)
- Department of Surgery, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA;
- Wake Forest School of Medicine Comprehensive Cancer Center, Winston-Salem, NC 27157, USA
| | - Pierre L. Triozzi
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; (E.R.S.); (K.L.C.); (P.L.T.)
- Wake Forest School of Medicine Comprehensive Cancer Center, Winston-Salem, NC 27157, USA
- Department of Hematology and Oncology, Wake Forest School of Medicine Comprehensive Cancer Center, Winston-Salem, NC 27157, USA
| | - David R. Soto-Pantoja
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; (E.R.S.); (K.L.C.); (P.L.T.)
- Department of Surgery, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA;
- Wake Forest School of Medicine Comprehensive Cancer Center, Winston-Salem, NC 27157, USA
- Department of Radiation Oncology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
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Reinfeld BI, Rathmell WK, Kim TK, Rathmell JC. The therapeutic implications of immunosuppressive tumor aerobic glycolysis. Cell Mol Immunol 2022; 19:46-58. [PMID: 34239083 PMCID: PMC8752729 DOI: 10.1038/s41423-021-00727-3] [Citation(s) in RCA: 64] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 05/27/2021] [Indexed: 02/06/2023] Open
Abstract
In 2011, Hanahan and Weinberg added "Deregulating Cellular Energetics" and "Avoiding Immune Destruction" to the six previous hallmarks of cancer. Since this seminal paper, there has been a growing consensus that these new hallmarks are not mutually exclusive but rather interdependent. The following review summarizes how founding genetic events for tumorigenesis ultimately increase tumor cell glycolysis, which not only supports the metabolic demands of malignancy but also provides an immunoprotective niche, promoting malignant cell proliferation, maintenance and progression. The mechanisms by which altered metabolism contributes to immune impairment are multifactorial: (1) the metabolic demands of proliferating tumor cells and activated immune cells are similar, thus creating a situation where immune cells may be in competition for key nutrients; (2) the metabolic byproducts of aerobic glycolysis directly inhibit antitumor immunity while promoting a regulatory immune phenotype; and (3) the gene programs associated with the upregulation of glycolysis also result in the generation of immunosuppressive cytokines and metabolites. From this perspective, we shed light on important considerations for the development of new classes of agents targeting cancer metabolism. These types of therapies can impair tumor growth but also pose a significant risk of stifling antitumor immunity.
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Affiliation(s)
- Bradley I Reinfeld
- Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - W Kimryn Rathmell
- Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Tae Kon Kim
- Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Jeffrey C Rathmell
- Vanderbilt Center for Immunobiology, Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
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34
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Importance of T, NK, CAR T and CAR NK Cell Metabolic Fitness for Effective Anti-Cancer Therapy: A Continuous Learning Process Allowing the Optimization of T, NK and CAR-Based Anti-Cancer Therapies. Cancers (Basel) 2021; 14:cancers14010183. [PMID: 35008348 PMCID: PMC8782435 DOI: 10.3390/cancers14010183] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 12/18/2021] [Accepted: 12/29/2021] [Indexed: 12/18/2022] Open
Abstract
Simple Summary Cancer treatments are evolving at a very rapid pace. Some of the most novel anti-cancer medicines under development rely on the modification of immune cells in order to transform them into potent tumor-killing cells. However, the tumor microenvironment (TME) is competing for nutrients with these harnessed immune cells and therefore paralyzes their metabolic effective and active anti-cancer activities. Here we describe strategies to overcome these hurdles imposed on immune cell activity, which lead to therapeutic approaches to enhance metabolic fitness of the patient’s immune system with the objective to improve their anti-cancer capacity. Abstract Chimeric antigen receptor (CAR) T and CAR NK cell therapies opened new avenues for cancer treatment. Although original successes of CAR T and CAR NK cells for the treatment of hematological malignancies were extraordinary, several obstacles have since been revealed, in particular their use for the treatment of solid cancers. The tumor microenvironment (TME) is competing for nutrients with T and NK cells and their CAR-expressing counterparts, paralyzing their metabolic effective and active states. Consequently, this can lead to alterations in their anti-tumoral capacity and persistence in vivo. High glucose uptake and the depletion of key amino acids by the TME can deprive T and NK cells of energy and building blocks, which turns them into a state of anergy, where they are unable to exert cytotoxic activity against cancer cells. This is especially true in the context of an immune-suppressive TME. In order to re-invigorate the T, NK, CAR T and CAR NK cell-mediated antitumor response, the field is now attempting to understand how metabolic pathways might change T and NK responses and functions, as well as those from their CAR-expressing partners. This revealed ways to metabolically rewire these cells by using metabolic enhancers or optimizing pre-infusion in vitro cultures of these cells. Importantly, next-generation CAR T and CAR NK products might include in the future the necessary metabolic requirements by improving their design, manufacturing process and other parameters. This will allow the overcoming of current limitations due to their interaction with the suppressive TME. In a clinical setting, this might improve their anti-cancer effector activity in synergy with immunotherapies. In this review, we discuss how the tumor cells and TME interfere with T and NK cell metabolic requirements. This may potentially lead to therapeutic approaches that enhance the metabolic fitness of CAR T and CAR NK cells, with the objective to improve their anti-cancer capacity.
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35
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Johnson RL, Cummings M, Thangavelu A, Theophilou G, de Jong D, Orsi NM. Barriers to Immunotherapy in Ovarian Cancer: Metabolic, Genomic, and Immune Perturbations in the Tumour Microenvironment. Cancers (Basel) 2021; 13:6231. [PMID: 34944851 PMCID: PMC8699358 DOI: 10.3390/cancers13246231] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 12/03/2021] [Accepted: 12/07/2021] [Indexed: 02/07/2023] Open
Abstract
A lack of explicit early clinical signs and effective screening measures mean that ovarian cancer (OC) often presents as advanced, incurable disease. While conventional treatment combines maximal cytoreductive surgery and platinum-based chemotherapy, patients frequently develop chemoresistance and disease recurrence. The clinical application of immune checkpoint blockade (ICB) aims to restore anti-cancer T-cell function in the tumour microenvironment (TME). Disappointingly, even though tumour infiltrating lymphocytes are associated with superior survival in OC, ICB has offered limited therapeutic benefits. Herein, we discuss specific TME features that prevent ICB from reaching its full potential, focussing in particular on the challenges created by immune, genomic and metabolic alterations. We explore both recent and current therapeutic strategies aiming to overcome these hurdles, including the synergistic effect of combination treatments with immune-based strategies and review the status quo of current clinical trials aiming to maximise the success of immunotherapy in OC.
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Affiliation(s)
- Racheal Louise Johnson
- Department Gynaecological Oncology, St. James’s University Hospital, Leeds LS9 7TF, UK; (A.T.); (G.T.); (D.d.J.)
| | - Michele Cummings
- Leeds Institute of Medical Research, St. James’s University Hospital, Leeds LS9 7TF, UK; (M.C.); (N.M.O.)
| | - Amudha Thangavelu
- Department Gynaecological Oncology, St. James’s University Hospital, Leeds LS9 7TF, UK; (A.T.); (G.T.); (D.d.J.)
| | - Georgios Theophilou
- Department Gynaecological Oncology, St. James’s University Hospital, Leeds LS9 7TF, UK; (A.T.); (G.T.); (D.d.J.)
| | - Diederick de Jong
- Department Gynaecological Oncology, St. James’s University Hospital, Leeds LS9 7TF, UK; (A.T.); (G.T.); (D.d.J.)
| | - Nicolas Michel Orsi
- Leeds Institute of Medical Research, St. James’s University Hospital, Leeds LS9 7TF, UK; (M.C.); (N.M.O.)
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36
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Zhang M, Jin X, Sun R, Xiong X, Wang J, Xie D, Zhao M. Optimization of metabolism to improve efficacy during CAR-T cell manufacturing. J Transl Med 2021; 19:499. [PMID: 34876185 PMCID: PMC8650271 DOI: 10.1186/s12967-021-03165-x] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 11/23/2021] [Indexed: 12/12/2022] Open
Abstract
Chimeric antigen receptor T cell (CAR-T cell) therapy is a relatively new, effective, and rapidly evolving therapeutic for adoptive immunotherapies. Although it has achieved remarkable effect in hematological malignancies, there are some problems that remain to be resolved. For example, there are high recurrence rates and poor efficacy in solid tumors. In this review, we first briefly describe the metabolic re-editing of T cells and the changes in metabolism during the preparation of CAR-T cells. Furthermore, we summarize the latest developments and newest strategies to improve the metabolic adaptability and antitumor activity of CAR-T cells in vitro and in vivo.
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Affiliation(s)
- Meng Zhang
- First Center Clinical College, Tianjin Medical University, Tianjin, 300192, China
| | - Xin Jin
- Department of Hematology, Tianjin First Central Hospital, Tianjin, 300192, China
| | - Rui Sun
- Department of Hematology, Tianjin First Central Hospital, Tianjin, 300192, China.,School of Medicine, Nankai University, Tianjin, 300071, China
| | - Xia Xiong
- First Center Clinical College, Tianjin Medical University, Tianjin, 300192, China
| | - Jiaxi Wang
- First Center Clinical College, Tianjin Medical University, Tianjin, 300192, China
| | - Danni Xie
- First Center Clinical College, Tianjin Medical University, Tianjin, 300192, China
| | - MingFeng Zhao
- Department of Hematology, Tianjin First Central Hospital, Tianjin, 300192, China.
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37
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Pietrobon V, Todd LA, Goswami A, Stefanson O, Yang Z, Marincola F. Improving CAR T-Cell Persistence. Int J Mol Sci 2021; 22:ijms221910828. [PMID: 34639168 PMCID: PMC8509430 DOI: 10.3390/ijms221910828] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 09/28/2021] [Accepted: 09/30/2021] [Indexed: 12/15/2022] Open
Abstract
Over the last decade remarkable progress has been made in enhancing the efficacy of CAR T therapies. However, the clinical benefits are still limited, especially in solid tumors. Even in hematological settings, patients that respond to CAR T therapies remain at risk of relapsing due to several factors including poor T-cell expansion and lack of long-term persistence after adoptive transfer. This issue is even more evident in solid tumors, as the tumor microenvironment negatively influences the survival, infiltration, and activity of T-cells. Limited persistence remains a significant hindrance to the development of effective CAR T therapies due to several determinants, which are encountered from the cell manufacturing step and onwards. CAR design and ex vivo manipulation, including culture conditions, may play a pivotal role. Moreover, previous chemotherapy and lymphodepleting treatments may play a relevant role. In this review, the main causes for decreased persistence of CAR T-cells in patients will be discussed, focusing on the molecular mechanisms underlying T-cell exhaustion. The approaches taken so far to overcome these limitations and to create exhaustion-resistant T-cells will be described. We will also examine the knowledge gained from several key clinical trials and highlight the molecular mechanisms determining T-cell stemness, as promoting stemness may represent an attractive approach to improve T-cell therapies.
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Affiliation(s)
- Violena Pietrobon
- Refuge Biotechnologies, Inc., Menlo Park, CA 94025, USA; (A.G.); (O.S.); (Z.Y.)
- Correspondence: (V.P.); (F.M.)
| | - Lauren Anne Todd
- Department of Biology, Faculty of Science, University of Waterloo, Waterloo, ON N2L 3G1, Canada;
| | - Anghsumala Goswami
- Refuge Biotechnologies, Inc., Menlo Park, CA 94025, USA; (A.G.); (O.S.); (Z.Y.)
| | - Ofir Stefanson
- Refuge Biotechnologies, Inc., Menlo Park, CA 94025, USA; (A.G.); (O.S.); (Z.Y.)
| | - Zhifen Yang
- Refuge Biotechnologies, Inc., Menlo Park, CA 94025, USA; (A.G.); (O.S.); (Z.Y.)
| | - Francesco Marincola
- Kite Pharma, Inc., Santa Monica, CA 90404, USA
- Correspondence: (V.P.); (F.M.)
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38
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Kim SH, Singh R, Han C, Cho E, Kim YI, Lee DG, Kim YH, Kim SS, Shin DH, You HJ, Lee HW, Kwon BS, Choi BK. Chronic activation of 4-1BB signaling induces granuloma development in tumor-draining lymph nodes that is detrimental to subsequent CD8 + T cell responses. Cell Mol Immunol 2021; 18:1956-1968. [PMID: 32868911 PMCID: PMC8322392 DOI: 10.1038/s41423-020-00533-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 08/11/2020] [Indexed: 11/09/2022] Open
Abstract
The antitumor capabilities of agonistic anti-4-1BB mAbs have made them an attractive target for tumor immunotherapy. However, the adverse side effects associated with agonist antibodies have hindered their clinical development. Here, we aimed to study the immune-related adverse events of repeated doses and long-term use of agonistic anti-4-1BB mAbs. We show that chronic activation of 4-1BB signals induced the accumulation of IFN-γ-producing PD-1+CD8+ T cells in the secondary lymphoid organs of tumor-bearing mice by increasing the number of dividing CD8+ T cells, which was beneficial for suppressing tumor growth in the early phase of anti-4-1BB induction. However, repeated exposure to anti-4-1BB mAbs led to granuloma development in tumor-draining lymph nodes (TDLNs) of mice due to recruitment and accumulation of macrophages via the CD8+ T cell-IFN-γ axis. This was accompanied by excessive lymph node swelling, which impaired the sequential activation of CD8+ T cells. Our data provide insights into the immune-related adverse events of long-term agonist 4-1BB antibody dosing, which should be considered during the clinical development of immunomodulating therapy.
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Affiliation(s)
- Seon-Hee Kim
- Division of Tumor Immunology, National Cancer Center, Goyang, 10408, Republic of Korea
| | - Rohit Singh
- Division of Tumor Immunology, National Cancer Center, Goyang, 10408, Republic of Korea
| | - Chungyong Han
- Division of Tumor Immunology, National Cancer Center, Goyang, 10408, Republic of Korea
| | - Eunjung Cho
- Division of Tumor Immunology, National Cancer Center, Goyang, 10408, Republic of Korea
| | - Yu I Kim
- Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, 10408, Republic of Korea
| | - Don G Lee
- Biomedicine Production Branch, Program for Immunotherapy Research, Goyang, 10408, Republic of Korea
| | - Young H Kim
- Division of Tumor Immunology, National Cancer Center, Goyang, 10408, Republic of Korea
- Eutilex Institute for Biomedical Research, Eutilex, Co., Ltd., Seoul, 08594, Republic of Korea
| | - Sang Soo Kim
- Division of Convergence Technology, National Cancer Center, Goyang, 10408, Republic of Korea
| | - Dong Hoon Shin
- Division of Translational Science, National Cancer Center, Goyang, 10408, Republic of Korea
| | - Hye Jin You
- Division of Translational Science, National Cancer Center, Goyang, 10408, Republic of Korea
| | - Hyeon-Woo Lee
- Institute of Oral Biology, School of Dentistry, Graduate School, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Byoung S Kwon
- Eutilex Institute for Biomedical Research, Eutilex, Co., Ltd., Seoul, 08594, Republic of Korea
- Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA, 70112, USA
| | - Beom K Choi
- Biomedicine Production Branch, Program for Immunotherapy Research, Goyang, 10408, Republic of Korea.
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39
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Madden MZ, Rathmell JC. The Complex Integration of T-cell Metabolism and Immunotherapy. Cancer Discov 2021; 11:1636-1643. [PMID: 33795235 PMCID: PMC8295173 DOI: 10.1158/2159-8290.cd-20-0569] [Citation(s) in RCA: 91] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 01/19/2021] [Accepted: 01/27/2021] [Indexed: 12/12/2022]
Abstract
Immune oncology approaches of adoptive cell therapy and immune checkpoint blockade aim to activate T cells to eliminate tumors. Normal stimulation of resting T cells induces metabolic reprogramming from catabolic and oxidative metabolism to aerobic glycolysis in effector T cells, and back to oxidative metabolism in long-lived memory cells. These metabolic reprogramming events are now appreciated to be essential aspects of T-cell function and fate. Here, we review these transitions, how they are disrupted by T-cell interactions with tumors and the tumor microenvironment, and how they can inform immune oncology to enhance T-cell function against tumors. SIGNIFICANCE: T-cell metabolism plays a central role in T-cell fate yet is altered in cancer in ways that can suppress antitumor immunity. Here, we discuss challenges and opportunities to stimulate effector T-cell metabolism and improve cancer immunotherapy.
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Affiliation(s)
- Matthew Z Madden
- Vanderbilt Center for Immunobiology, Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Jeffrey C Rathmell
- Vanderbilt Center for Immunobiology, Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.
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40
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Metabolic Modulation of Immunity: A New Concept in Cancer Immunotherapy. Cell Rep 2021; 32:107848. [PMID: 32640218 DOI: 10.1016/j.celrep.2020.107848] [Citation(s) in RCA: 106] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 04/22/2020] [Accepted: 06/11/2020] [Indexed: 12/18/2022] Open
Abstract
Immunotherapy shifted the paradigm of cancer treatment. The clinical approval of immune checkpoint blockade and adoptive cell transfer led to considerable success in several tumor types. However, for a significant number of patients, these therapies have proven ineffective. Growing evidence shows that the metabolic requirements of immune cells in the tumor microenvironment (TME) greatly influence the success of immunotherapy. It is well established that the TME influences energy consumption and metabolic reprogramming of immune cells, often inducing them to become tolerogenic and inefficient in cancer cell eradication. Increasing nutrient availability using pharmacological modulators of metabolism or antibodies targeting specific immune receptors are strategies that support energetic rewiring of immune cells and boost their anti-tumor capacity. In this review, we describe the metabolic features of the diverse immune cell types in the context of the TME and discuss how these immunomodulatory strategies could synergize with immunotherapy to circumvent its current limitations.
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41
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Roy DG, Kaymak I, Williams KS, Ma EH, Jones RG. Immunometabolism in the Tumor Microenvironment. ANNUAL REVIEW OF CANCER BIOLOGY 2021; 5:137-159. [DOI: 10.1146/annurev-cancerbio-030518-055817] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Advances in immunotherapy have underscored the importance of antitumor immune responses in controlling cancer. However, the tumor microenvironment (TME) imposes several obstacles to the proper function of immune cells, including a metabolically challenging and immunosuppressive microenvironment. The increased metabolic activity of tumor cells can lead to the depletion of key nutrients required by immune cells and the accumulation of byproducts that hamper antitumor immunity. Furthermore, the presence of suppressive immune cells, such as regulatory T cells and myeloid-derived suppressor cells, and the expression of immune inhibitory receptors can negatively impact immune cell metabolism and function. This review summarizes the metabolic reprogramming that is characteristic of various immune cell subsets, discusses how the metabolism and function of immune cells are shaped by the TME, and highlights how therapeutic interventions aimed at improving the metabolic fitness of immune cells and alleviating the metabolic constraints in the TME can boost antitumor immunity.
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Affiliation(s)
- Dominic G. Roy
- Goodman Cancer Research Centre, Faculty of Medicine, McGill University, Montreal, Quebec H3A 1A3, Canada
| | - Irem Kaymak
- Metabolic and Nutritional Programming, Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA
| | - Kelsey S. Williams
- Metabolic and Nutritional Programming, Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA
| | - Eric H. Ma
- Metabolic and Nutritional Programming, Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA
| | - Russell G. Jones
- Metabolic and Nutritional Programming, Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA
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42
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He S, Cai T, Yuan J, Zheng X, Yang W. Lipid Metabolism in Tumor-Infiltrating T Cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1316:149-167. [PMID: 33740249 DOI: 10.1007/978-981-33-6785-2_10] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
T cells recognize "foreign" antigens and induce durable humoral and cellular immune responses, which are indispensable for defending pathogens, as well as maintaining the integrity and homeostasis of tissues and organs. T cells are the major immune cell population in the tumor microenvironment which play a critical role in the antitumor immune response and cancer immune surveillance. Defective immune response of tumor-infiltrating T cells is the main cause of cancer immune evasion. The antitumor response of T cells is affected by multiple factors in the tumor microenvironment, including immunosuppressive cells, immune inhibitory cytokines, tumor-derived suppressive signals like PD-L1, immnuogenicity of tumor cells, as well as metabolic factors like hypoxia and nutrient deprivation. Abundant studies in past decades have proved the metabolic regulations of the immune response of T cells and the tumor-infiltrating T cells. In this chapter, we will discuss the regulations of the antitumor response of tumor-infiltrating T cells by lipid metabolism, which is one of the main components of metabolic regulation.
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Affiliation(s)
- Shangwen He
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Ting Cai
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Juanjuan Yuan
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Xiaojun Zheng
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Wei Yang
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
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CD137 (4-1BB) stimulation leads to metabolic and functional reprogramming of human monocytes/macrophages enhancing their tumoricidal activity. Leukemia 2021; 35:3482-3496. [PMID: 34021248 PMCID: PMC8632678 DOI: 10.1038/s41375-021-01287-1] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 04/29/2021] [Accepted: 05/05/2021] [Indexed: 02/04/2023]
Abstract
Immunotherapies have heralded a new era in the cancer treatment. In addition to checkpoint inhibitors, agonistic antibodies against co-stimulatory immune receptors hold the potential to invoke efficient antitumor immunity. Targeting CD137 has gained momentum based on its ability to drive NK- and T-cell-based responses. CD137-engaging mAbs have already entered clinical trials for different types of tumors showing promising results. Despite the efforts to translate CD137-mediated immunotherapy into clinical practice, little remains known regarding the role of CD137 in human monocytes/macrophages.We found CD137 being expressed on monocytes of healthy controls and at even higher levels in patients with multiple myeloma or CLL. CD137HI(GH) monocytes displayed a distinct phenotypic, transcriptomic, and metabolic profile. They possessed an increased phagocytic capacity enabling superior antibody-dependent phagocytosis (ADPC) of multiple myeloma and lymphoma cells that were treated with anti-CD38 or anti-CD20 mAbs. Triggering CD137 promoted both metabolic and tumoricidal activity in an extracellular signal-regulated kinase (ERK)-dependent fashion. In addition, we observed a phenotypic, transcriptomic, and functional skewing towards a M1-like phenotype.Overall, we introduce CD137 as a positive immune checkpoint on human monocytes/macrophages, which can have therapeutic implications especially in view of synergistic effects when combining CD137 agonists with tumor-targeting antibodies.
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Choi BK, Lee HW. The Murine CD137/CD137 Ligand Signalosome: A Signal Platform Generating Signal Complexity. Front Immunol 2020; 11:553715. [PMID: 33362756 PMCID: PMC7758191 DOI: 10.3389/fimmu.2020.553715] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 11/06/2020] [Indexed: 12/21/2022] Open
Abstract
CD137, a member of the TNFR family, is a costimulatory receptor, and CD137L, a member of the TNF family, is its ligand. Studies using CD137- and CD137L-deficient mice and antibodies against CD137 and CD137L have revealed the diverse and paradoxical effects of these two proteins in various cancers, autoimmunity, infections, and inflammation. Both their cellular diversity and their spatiotemporal expression patterns indicate that they mediate complex immune responses. This intricacy is further enhanced by the bidirectional signal transduction events that occur when these two proteins interact in various types of immune cells. Here, we review the biology of murine CD137/CD137L, particularly, the complexity of their proximal signaling pathways, and speculate on their roles in immune responses.
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Affiliation(s)
- Beom K Choi
- Biomedicine Production Branch, Program for Immunotherapy Research, National Cancer Center, Goyang, South Korea
| | - Hyeon-Woo Lee
- Department of Pharmacology, School of Dentistry, Graduate School, Institute of Oral Biology, Kyung Hee University, Seoul, South Korea
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45
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Oda SK, Anderson KG, Ravikumar P, Bonson P, Garcia NM, Jenkins CM, Zhuang S, Daman AW, Chiu EY, Bates BM, Greenberg PD. A Fas-4-1BB fusion protein converts a death to a pro-survival signal and enhances T cell therapy. J Exp Med 2020; 217:e20191166. [PMID: 32860705 PMCID: PMC7953733 DOI: 10.1084/jem.20191166] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 06/02/2020] [Accepted: 08/03/2020] [Indexed: 12/20/2022] Open
Abstract
Adoptive T cell therapy (ACT) with genetically modified T cells has shown impressive results against some hematologic cancers, but efficacy in solid tumors can be limited by restrictive tumor microenvironments (TMEs). For example, Fas ligand is commonly overexpressed in TMEs and induces apoptosis in tumor-infiltrating, Fas receptor-positive lymphocytes. We engineered immunomodulatory fusion proteins (IFPs) to enhance ACT efficacy, combining an inhibitory receptor ectodomain with a costimulatory endodomain to convert negative into positive signals. We developed a Fas-4-1BB IFP that replaces the Fas intracellular tail with costimulatory 4-1BB. Fas-4-1BB IFP-engineered murine T cells exhibited increased pro-survival signaling, proliferation, antitumor function, and altered metabolism in vitro. In vivo, Fas-4-1BB ACT eradicated leukemia and significantly improved survival in the aggressive KPC pancreatic cancer model. Fas-4-1BB IFP expression also enhanced primary human T cell function in vitro. Thus, Fas-4-1BB IFP expression is a novel strategy to improve multiple T cell functions and enhance ACT against solid tumors and hematologic malignancies.
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Affiliation(s)
- Shannon K. Oda
- Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA
| | | | - Pranali Ravikumar
- Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Patrick Bonson
- Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Nicolas M. Garcia
- Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Cody M. Jenkins
- Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Summer Zhuang
- Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Andrew W. Daman
- Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Edison Y. Chiu
- Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Breanna M. Bates
- Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Philip D. Greenberg
- Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA
- Department of Medicine/Oncology, University of Washington, Seattle, WA
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46
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Rostamian H, Fallah-Mehrjardi K, Khakpoor-Koosheh M, Pawelek JM, Hadjati J, Brown CE, Mirzaei HR. A metabolic switch to memory CAR T cells: Implications for cancer treatment. Cancer Lett 2020; 500:107-118. [PMID: 33290868 DOI: 10.1016/j.canlet.2020.12.004] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 12/01/2020] [Accepted: 12/02/2020] [Indexed: 12/27/2022]
Abstract
Therapeutic efficacy of chimeric antigen receptor (CAR) T cells is associated with their expansion, persistence and effector function. Although CAR T cell therapy has shown remarkable therapeutic effects in hematological malignancies, its therapeutic efficacy has been limited in some types of cancers - in particular, solid tumors - partially due to the cells' inability to persist and the acquisition of T cell dysfunction within a harsh immunosuppressive tumor microenvironment. Therefore, it would be expected that generation of CAR T cells with intrinsic properties for functional longevity, such as the cells with early-memory phenotypes, could beneficially enhance antitumor immunity. Furthermore, because the metabolic pathways of CAR T cells help determine cellular differentiation and lifespan, therapies targeting such pathways like glycolysis and oxidative phosphorylation, can alter CAR T cell fate and durability within tumors. Here we discuss how reprogramming of CAR T cell metabolism and metabolic switch to memory CAR T cells influences their antitumor activity. We also offer potential strategies for targeting these metabolic circuits in the setting of adoptive CAR T cell therapy, aiming to better unleash the potential of adoptive CAR T cell therapy in the clinic.
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Affiliation(s)
- Hosein Rostamian
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Keyvan Fallah-Mehrjardi
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Khakpoor-Koosheh
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - John M Pawelek
- Department of Dermatology and the Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA
| | - Jamshid Hadjati
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Christine E Brown
- Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, CA, 91010, USA; Department of Immuno-Oncology, City of Hope Beckman Research Institute, Duarte, CA, 91010, USA.
| | - Hamid R Mirzaei
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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Peña-Asensio J, Sanz-de-Villalobos E, Miquel J, Larrubia JR. Tumor necrosis family receptor superfamily member 9/tumor necrosis factor receptor-associated factor 1 pathway on hepatitis C viral persistence and natural history. World J Hepatol 2020; 12:754-765. [PMID: 33200014 PMCID: PMC7643212 DOI: 10.4254/wjh.v12.i10.754] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Revised: 08/01/2020] [Accepted: 09/25/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection is an excellent immunological model for understanding the mechanisms developed by non-cytopathic viruses and tumors to evade the adaptative immune response. The antigen-specific cytotoxic T cell response is essential for keeping HCV under control, but during persistent infection, these cells become exhausted or even deleted. The exhaustion process is progressive and depends on the infection duration and level of antigenemia. During high antigenic load and long duration of infection, T cells become extremely exhausted and ultimately disappear due to apoptosis. The development of exhaustion involves the impairment of positive co-stimulation induced by regulatory cytokines, such as transforming growth factor beta 1. This cytokine downregulates tumor necrosis factor receptor (TNFR)-associated factor 1 (TRAF1), the signal transducer of the T cell co-stimulatory molecule TNFR superfamily member 9 (known as 4-1BB). This impairment correlates with the low reactivity of T cells and an exhaustion phenotype. Treatment with interleukin-7 in vitro restores TRAF1 expression and rescues T cell effector function. The process of TRAF1 loss and its in vitro recovery is hierarchical, and more affected by severe disease progression. In conclusion, TRAF1 dynamics on T cells define a new pathogenic model that describes some aspects of the natural history of HCV, and sheds light on novel immunotherapy strategies for chronic viral infections and cancer.
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Affiliation(s)
- Julia Peña-Asensio
- Department of Systems Biology, Guadalajara University Hospital. University of Alcalá, Guadalajara E-19002, Guadalajara, Spain
| | - Eduardo Sanz-de-Villalobos
- Translational Hepatology Unit, Guadalajara University Hospital, University of Alcalá, Guadalajara E-19002, Guadalajara, Spain
| | - Joaquín Miquel
- Translational Hepatology Unit, Guadalajara University Hospital, University of Alcalá, Guadalajara E-19002, Guadalajara, Spain
| | - Juan Ramón Larrubia
- Translational Hepatology Unit, Guadalajara University Hospital, University of Alcalá, Guadalajara E-19002, Guadalajara, Spain
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48
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Terrén I, Orrantia A, Vitallé J, Astarloa-Pando G, Zenarruzabeitia O, Borrego F. Modulating NK cell metabolism for cancer immunotherapy. Semin Hematol 2020; 57:213-224. [PMID: 33256914 DOI: 10.1053/j.seminhematol.2020.10.003] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 09/18/2020] [Accepted: 10/14/2020] [Indexed: 02/08/2023]
Abstract
Natural killer (NK) cells are lymphocytes with potent antitumor functions and, therefore, multiple NK cell-based cancer immunotherapies have been developed and are currently being tested. However, there is a necessity to find new means to improve these therapies, and immunometabolism represents an attractive target. NK cell effector functions are intricately linked to their metabolism, and modulating the latter could be the key to release their full potential. In this review, we have summarized how NK cell metabolism is regulated during some processes, such as maturation, viral infection, and cytokine stimulation. Additionally, we provide an overview of how NK cell metabolism is affected by current therapeutic approaches aimed to promote NK cell expansion and/or to increase their effector functions. We have also recapitulated several strategies that could help alleviating the metabolic impairment that characterizes tumor-infiltrating NK cells, and thus increase or restore their effector functions. Furthermore, we have reviewed several therapeutic approaches targeting cancer metabolism that could synergize with NK cell-based cancer immunotherapies, and thus enhance their efficacy.
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Affiliation(s)
- Iñigo Terrén
- Biocruces Bizkaia Health Research Institute, Immunopathology Group, Barakaldo, Spain
| | - Ane Orrantia
- Biocruces Bizkaia Health Research Institute, Immunopathology Group, Barakaldo, Spain
| | - Joana Vitallé
- Biocruces Bizkaia Health Research Institute, Immunopathology Group, Barakaldo, Spain
| | | | - Olatz Zenarruzabeitia
- Biocruces Bizkaia Health Research Institute, Immunopathology Group, Barakaldo, Spain.
| | - Francisco Borrego
- Biocruces Bizkaia Health Research Institute, Immunopathology Group, Barakaldo, Spain; Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
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49
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Teijeira A, Garasa S, Etxeberria I, Gato-Cañas M, Melero I, Delgoffe GM. Metabolic Consequences of T-cell Costimulation in Anticancer Immunity. Cancer Immunol Res 2020; 7:1564-1569. [PMID: 31575551 DOI: 10.1158/2326-6066.cir-19-0115] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
T-cell functional behavior and performance are closely regulated by nutrient availability and the control of metabolism within the T cell. T cells have distinct energetic and anabolic needs when nascently activated, actively proliferating, in naïveté, or in a resting, memory state. As a consequence, bioenergetics are key for T cells to mount adequate immune responses in health and disease. Solid tumors are particularly hostile metabolic environments, characterized by low glucose concentration, hypoxia, and low pH. These metabolic conditions in the tumor are known to hinder antitumor immune responses of T cells by limiting nutrient availability and energetic efficiency. In such immunosuppressive environments, artificial modulation of glycolysis, mitochondrial respiratory capabilities, and fatty acid β-oxidation are known to enhance antitumor performance. Reportedly, costimulatory molecules, such as CD28 and CD137, are important regulators of metabolic routes in T cells. In this sense, different costimulatory signals and cytokines induce diverse metabolic changes that critically involve mitochondrial mass and function. For instance, the efficacy of chimeric antigen receptors (CAR) encompassing costimulatory domains, agonist antibodies to costimulatory receptors, and checkpoint inhibitors depends on the associated metabolic events in immune cells. Here, we review the metabolic changes that costimulatory receptors can promote in T cells and the potential consequences for cancer immunotherapy. Our focus is mostly on discoveries regarding the physiology and pharmacology of IL15, CD28, PD-1, and CD137 (4-1BB).
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Affiliation(s)
- Alvaro Teijeira
- Program of Immunology and Immunotherapy, CIMA Universidad de Navarra, Pamplona, Spain. .,Navarra Institute for Health Research (IDISNA), Pamplona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Saray Garasa
- Program of Immunology and Immunotherapy, CIMA Universidad de Navarra, Pamplona, Spain.,Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Inaki Etxeberria
- Program of Immunology and Immunotherapy, CIMA Universidad de Navarra, Pamplona, Spain.,Navarra Institute for Health Research (IDISNA), Pamplona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Maria Gato-Cañas
- Program of Immunology and Immunotherapy, CIMA Universidad de Navarra, Pamplona, Spain.,Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Ignacio Melero
- Program of Immunology and Immunotherapy, CIMA Universidad de Navarra, Pamplona, Spain.,Navarra Institute for Health Research (IDISNA), Pamplona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.,Department of Immunology and Immunotherapy, Clínica Universidad de Navarra, Pamplona, Spain
| | - Greg M Delgoffe
- Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania.,Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania
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50
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Flerin NC, Pinioti S, Menga A, Castegna A, Mazzone M. Impact of Immunometabolism on Cancer Metastasis: A Focus on T Cells and Macrophages. Cold Spring Harb Perspect Med 2020; 10:a037044. [PMID: 31615868 PMCID: PMC7461771 DOI: 10.1101/cshperspect.a037044] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Despite improved treatment options, cancer remains the leading cause of morbidity and mortality worldwide, with 90% of this mortality correlated to the development of metastasis. Since metastasis has such an impact on treatment success, disease outcome, and global health, it is important to understand the different steps and factors playing key roles in this process, how these factors relate to immune cell function and how we can target metabolic processes at different steps of metastasis in order to improve cancer treatment and patient prognosis. Recent insights in immunometabolism direct to promising therapeutic targets for cancer treatment, however, the specific contribution of metabolism on antitumor immunity in different metastatic niches warrant further investigation. Here, we provide an overview of what is so far known in the field of immunometabolism at different steps of the metastatic cascade, and what may represent the next steps forward. Focusing on metabolic checkpoints in order to translate these findings from in vitro and mouse studies to the clinic has the potential to revolutionize cancer immunotherapy and greatly improve patient prognosis.
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Affiliation(s)
- Nina C Flerin
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven B3000, Belgium
- Department of Oncology, Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, KU Leuven, Leuven B3000, Belgium
| | - Sotiria Pinioti
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven B3000, Belgium
- Department of Oncology, Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, KU Leuven, Leuven B3000, Belgium
| | - Alessio Menga
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven B3000, Belgium
- Department of Oncology, Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, KU Leuven, Leuven B3000, Belgium
| | - Alessandra Castegna
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari 70125, Italy
- IBIOM-CNR, Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council, Italy
| | - Massimiliano Mazzone
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven B3000, Belgium
- Department of Oncology, Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, KU Leuven, Leuven B3000, Belgium
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