Journal Articles

Metabolism and Microbiota

Metabolic pathways and metabolites affecting immune cell function and influence of microbiota on response to cancer immunotherapy

Canonical TGF-beta Signaling Pathway Represses Human NK Cell Metabolism

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Cytokines stimulate rapid metabolic changes in human NK cells, including increases in both glycolysis and oxidative phosphorylation pathways. However, how these are subsequently regulated is not known. In this study, we demonstrate that TGF-beta can inhibit many of these metabolic changes, including oxidative phosphorylation, glycolytic capacity, and respiratory capacity. TGF-beta also inhibited cytokine-induced expression of the transferrin nutrient receptor CD71. In contrast to a recent report on murine NK cells, TGF-beta-mediated suppression of these metabolic responses did not involve the inhibition of the metabolic regulator mTORC1. Inhibition of the canonical TGF-beta signaling pathway was able to restore almost all metabolic and functional responses that were inhibited by TGF-beta. These data suggest that pharmacological inhibition of TGF-beta could provide a metabolic advantage to NK cells that is likely to result in improved functional responses. This has important implications for NK cell-based cancer immunotherapies.

Author Info: (1) School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland; and. (2) School of Biochemistry and Immunology, Trinity Biomedical

Author Info: (1) School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland; and. (2) School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland; and clair.gardiner@tcd.ie finlayd@tcd.ie. School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland. (3) School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland; and clair.gardiner@tcd.ie finlayd@tcd.ie.

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Does the gastrointestinal microbiome contribute to the "obesity paradox" in melanoma survival

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McQuade et al.(1) have recently reported that in male patients with metastatic melanoma, obesity at the onset of systemic treatment (targeted and immunotherapy) is not only associated with increased progression-free survival but also with improved overall survival when compared to patients with a normal body mass index (BMI). On the basis of these results the authors called for further research to confirm the association and investigate the potential mechanisms which underlie it. To this end, we would like to highlight one potentially important mechanism; the gut microbiome. Indeed several recent publications have reported that the gut microbiome may influence response to immune checkpoint therapy,(2,3) potentially improving treatment efficacy, and may predict which patients are at risk of developing potentially life-threatening side effects, including immune-mediated colitis.(4) In fact, the clinical efficacy of immunotherapy, specifically anti-CTLA-4 therapy, may depend on the composition of the gut bacteria flora in order to exert their anti-tumor effect.(5) This article is protected by copyright. All rights reserved.

Author Info: (1) Department of Dermatology, University of Lubeck, Lubeck, Germany. Centre for Dermatological Science, University of Manchester, Manchester, UK. (2) Centre for Dermatological Science, University of

Author Info: (1) Department of Dermatology, University of Lubeck, Lubeck, Germany. Centre for Dermatological Science, University of Manchester, Manchester, UK. (2) Centre for Dermatological Science, University of Manchester, Manchester, UK. (3) Department of Surgery, University Clinic of Heidelberg, Heidelberg, Germany. (4) Department of Dermatology, University of Lubeck, Lubeck, Germany. (5) Department of Dermatology, University of Lubeck, Lubeck, Germany.

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Fatty acid metabolism in CD8(+) T cell memory: Challenging current concepts

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CD8(+) T cells are key members of the adaptive immune response against infections and cancer. As we discuss in this review, these cells can present diverse metabolic requirements, which have been intensely studied during the past few years. Our current understanding suggests that aerobic glycolysis is a hallmark of activated CD8(+) T cells, while naive and memory (Tmem ) cells often rely on oxidative phosphorylation, and thus mitochondrial metabolism is a crucial determinant of CD8(+) Tmem cell development. Moreover, it has been proposed that CD8(+) Tmem cells have a specific requirement for the oxidation of long-chain fatty acids (LC-FAO), a process modulated in lymphocytes by the enzyme CPT1A. However, this notion relies heavily on the metabolic analysis of in vitro cultures and on chemical inhibition of CPT1A. Therefore, we introduce more recent studies using genetic models to demonstrate that CPT1A-mediated LC-FAO is dispensable for the development of CD8(+) T cell memory and protective immunity, and question the use of chemical inhibitors to target this enzyme. We discuss insights obtained from those and other studies analyzing the metabolic characteristics of CD8(+) Tmem cells, and emphasize how T cells exhibit flexibility in their choice of metabolic fuel.

Author Info: (1) Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover (MHH) and the Helmholtz

Author Info: (1) Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany. (2) Metabolism, Infection, and Immunity Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. (3) Department of Physiology, Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada. (4) Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany. (5) Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany.

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Mitochondrial morphological and functional reprogramming following CD137 (4-1BB) co-stimulation

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T and NK lymphocytes express CD137 (4-1BB), a costimulatory receptor of the TNFR family whose function is exploitable for cancer immunotherapy. Mitochondria regulate the function and survival of T lymphocytes. Herein, we show that CD137 costimulation provided by agonist mAb and CD137L (4-1BBL) induced mitochondria enlargement that resulted in enhanced mitochondrial mass and transmembrane potential in human and mouse CD8+ T cells. Such mitochondrial changes increased T-cell respiratory capacities and were critically dependent on mitochondrial fusion protein OPA-1 expression. Mass and function of mitochondria in tumor-reactive CD8+ T cells from cancer-bearing mice were invigorated by agonist mAb to CD137, whereas. mitochondrial baseline mass and function were depressed in CD137-deficient tumor reactive T-cells. Tumor rejection induced by the synergistic combination of adoptive T-cell therapy and agonistic anti-CD137 was critically dependent on OPA-1 expression in transferred CD8+ T cells. Moreover, stimulation of CD137 with CD137 mAb in short-term cultures of human tumor-infiltrating lymphocytes led to mitochondria enlargement and increased transmembrane potential. Collectively, these data point to a critical link between mitochondrial morphology and function and enhanced antitumor effector activity upon CD137 costimulation of T cells.

Author Info: (1) Oncology, Center for Applied Medical Research (CIMA). University of Navarra ateijeiras@unav.es. (2) Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University

Author Info: (1) Oncology, Center for Applied Medical Research (CIMA). University of Navarra ateijeiras@unav.es. (2) Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA). (3) Center for Applied Medical Research (CIMA), University of Navarra. (4) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA). (5) CIMA, CIBEREHD. (6) Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA). (7) MPA, CNIC. (8) Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA). (9) Cell Therapy Area and Immunology, CIMA and Clinica Universidad de Navarra. (10) Gene Therapy and Hepatology Unit, CIMA+ (Canada). (11) Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA). (12) Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA). (13) CNIC, Fundacion Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC). (14) Immunology, CIMA and CUN.

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Regulation of Immune Cell Functions by Metabolic Reprogramming

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Recent findings show that the metabolic status of immune cells can determine immune responses. Metabolic reprogramming between aerobic glycolysis and oxidative phosphorylation, previously speculated as exclusively observable in cancer cells, exists in various types of immune and stromal cells in many different pathological conditions other than cancer. The microenvironments of cancer, obese adipose, and wound-repairing tissues share common features of inflammatory reactions. In addition, the metabolic changes in macrophages and T cells are now regarded as crucial for the functional plasticity of the immune cells and responsible for the progression and regression of many pathological processes, notably cancer. It is possible that metabolic changes in the microenvironment induced by other cellular components are responsible for the functional plasticity of immune cells. This review explores the molecular mechanisms responsible for metabolic reprogramming in macrophages and T cells and also provides a summary of recent updates with regard to the functional modulation of the immune cells by metabolic changes in the microenvironment, notably the tumor microenvironment.

Author Info: (1) Department of Biochemistry, School of Medicine, Gachon University, Incheon 21999, Republic of Korea. Department of Health Sciences and Technology, Gachon Advanced Institute for Health

Author Info: (1) Department of Biochemistry, School of Medicine, Gachon University, Incheon 21999, Republic of Korea. Department of Health Sciences and Technology, Gachon Advanced Institute for Health Science and Technology, Gachon University, Incheon 21999, Republic of Korea.

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Obesity induced T cell dysfunction and implications for cancer immunotherapy

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Obesity has been shown to increase risk for a number of different disorders, including cancer. In addition, obesity is also associated with immune dysfunction, which could contribute to its strong association with other comorbidities. Recently, the immune system has been found to be heavily regulated by changes in metabolism. In particular, T cells are able to respond to intrinsic metabolic regulatory mechanisms, as well as extrinsic factors such as the changes in metabolite availability. The dysfunctional metabolic environment created by obesity could therefore have a direct impact on T cell responses. In this review, we highlight recent findings in the fields of T cell biology and obesity, with a focus on mechanisms driving T cell dysfunction and potential implications for immunotherapeutic treatment of cancer.

Author Info: (1) Department of Dermatology, UC Davis School of Medicine, Sacramento, CA 95816, USA. (2) Department of Dermatology, UC Davis School of Medicine, Sacramento, CA 95816

Author Info: (1) Department of Dermatology, UC Davis School of Medicine, Sacramento, CA 95816, USA. (2) Department of Dermatology, UC Davis School of Medicine, Sacramento, CA 95816, USA; Department of Internal Medicine, UC Davis School of Medicine, Sacramento, CA 95817, USA. Electronic address: wmjmurphy@ucdavis.edu.

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The role of hypoxia in shaping the recruitment of proangiogenic and immunosuppressive cells in the tumor microenvironment

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Hypoxia characterizes growing tumors and contributes significantly to their aggressiveness. Hypoxia-inducible factors (HIFs 1 and 2) are stabilized and act differentially as transcription factors on tumor growth and are responsible for important cancer hallmarks such as pathologic angiogenesis, cellular proliferation, apoptosis, differentiation and genetic instability as well as affecting tumor metabolism, tumor immune responses, invasion and metastasis. Taking into account the tumor tissue as a whole and considering the interplay of the various partners which react with hypoxia in the tumor site lead to reconsideration of the treatment strategies. Key limitations of treatment success result from the adaptation to the hypoxic milieu sustained by tumor anarchic angiogenesis. This raises immune tolerance by influencing the recruitment of immunosuppressive cells as bone marrow derived suppressor cells (MDSC) or by impairing the infiltration and killing of tumor cells by cytotoxic cells at the level of the endothelial cell wall of the hypoxic tumor vessels, as summarized in the schematic abstract.

Author Info: (1) INSERM (Institut National de la Sante et de la Recherche Medicale) UMR1186, Laboratory Integrative Tumor Immunology and Genetic Oncology, Villejuif, France. INSERM, Gustave Roussy

Author Info: (1) INSERM (Institut National de la Sante et de la Recherche Medicale) UMR1186, Laboratory Integrative Tumor Immunology and Genetic Oncology, Villejuif, France. INSERM, Gustave Roussy, Univ. Paris-Sud, Universite Paris-Saclay, Villejuif, France. Thumbay Institute for Precision Medicine and Translational Research - Gulf Medical University Ajman UAE. (2) Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany. (3) Laboratory of Molecular oncology, Military Institute of Medicine, Warsaw, Poland. Centre for Molecular Biophysics, CNRS, 45071, Orleans, France.

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Increased Tumor Glycolysis Characterizes Immune Resistance to Adoptive T Cell Therapy

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Adoptive T cell therapy (ACT) produces durable responses in some cancer patients; however, most tumors are refractory to ACT and the molecular mechanisms underlying resistance are unclear. Using two independent approaches, we identified tumor glycolysis as a pathway associated with immune resistance in melanoma. Glycolysis-related genes were upregulated in melanoma and lung cancer patient samples poorly infiltrated by T cells. Overexpression of glycolysis-related molecules impaired T cell killing of tumor cells, whereas inhibition of glycolysis enhanced T cell-mediated antitumor immunity in vitro and in vivo. Moreover, glycolysis-related gene expression was higher in melanoma tissues from ACT-refractory patients, and tumor cells derived from these patients exhibited higher glycolytic activity. We identified reduced levels of IRF1 and CXCL10 immunostimulatory molecules in highly glycolytic melanoma cells. Our findings demonstrate that tumor glycolysis is associated with the efficacy of ACT and identify the glycolysis pathway as a candidate target for combinatorial therapeutic intervention.

Author Info: (1) Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (2) Department of Melanoma Medical

Author Info: (1) Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (2) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (3) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (4) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (5) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (6) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (7) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (8) Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (9) Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (10) Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (11) Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (12) Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (13) Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (14) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (15) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (16) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (17) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (18) Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (19) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (20) Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (21) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (22) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (23) Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (24) Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (25) Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (26) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (27) Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. (28) Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (29) Department of Palliative, Rehabilitation and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (30) Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (31) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (32) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (33) Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (34) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (35) Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (36) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: phwu@mdanderson.org. (37) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: wpeng@mdanderson.org.

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Gut Microbiota Promotes Tumor Growth in Mice by Modulating Immune Response

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We studied the effects of gut microbiome depletion by oral antibiotics on tumor growth in subcutaneous and liver metastases model of pancreatic cancer, colon cancer and melanoma. Gut microbiome depletion significantly reduced tumor burden in all the models tested. However, depletion of gut microbiome did not reduce tumor growth in Rag1-knockout mice, which lack mature T and B cells. Flowcytometry analyses demonstrated that gut microbiome depletion led to significant increase in interferon gamma-producing T cells with corresponding decrease in interleukin 17A and interleukin 10-producing T cells. Our results suggest that gut microbiome modulation could emerge as a novel immunotherapeutic strategy.

Author Info: (1) Department of Surgery at Sylvester Comprehensive Cancer Center and University of Miami Miller School of Medicine, Miami, FL, 33136, USA. (2) Department of Surgery

Author Info: (1) Department of Surgery at Sylvester Comprehensive Cancer Center and University of Miami Miller School of Medicine, Miami, FL, 33136, USA. (2) Department of Surgery at Sylvester Comprehensive Cancer Center and University of Miami Miller School of Medicine, Miami, FL, 33136, USA. (3) Department of Surgery at Sylvester Comprehensive Cancer Center and University of Miami Miller School of Medicine, Miami, FL, 33136, USA. (4) Department of Surgery at Sylvester Comprehensive Cancer Center and University of Miami Miller School of Medicine, Miami, FL, 33136, USA. (5) Department of Surgery at Sylvester Comprehensive Cancer Center and University of Miami Miller School of Medicine, Miami, FL, 33136, USA. (6) Department of Surgery at Sylvester Comprehensive Cancer Center and University of Miami Miller School of Medicine, Miami, FL, 33136, USA. (7) Department of Surgery at Sylvester Comprehensive Cancer Center and University of Miami Miller School of Medicine, Miami, FL, 33136, USA. (8) Department of Surgery at Sylvester Comprehensive Cancer Center and University of Miami Miller School of Medicine, Miami, FL, 33136, USA. (9) Department of Surgery at Sylvester Comprehensive Cancer Center and University of Miami Miller School of Medicine, Miami, FL, 33136, USA. (10) Department of Surgery at Sylvester Comprehensive Cancer Center and University of Miami Miller School of Medicine, Miami, FL, 33136, USA. (11) Department of Surgery at Sylvester Comprehensive Cancer Center and University of Miami Miller School of Medicine, Miami, FL, 33136, USA. (12) Department of Surgery, University of Alabama, Birmingham, Alabama, USA. (13) Department of Surgery at Sylvester Comprehensive Cancer Center and University of Miami Miller School of Medicine, Miami, FL, 33136, USA. (14) Department of Surgery at Sylvester Comprehensive Cancer Center and University of Miami Miller School of Medicine, Miami, FL, 33136, USA. (15) Department of Surgery at Sylvester Comprehensive Cancer Center and University of Miami Miller School of Medicine, Miami, FL, 33136, USA. (16) Department of Surgery at Sylvester Comprehensive Cancer Center and University of Miami Miller School of Medicine, Miami, FL, 33136, USA. (17) Department of Surgery at Sylvester Comprehensive Cancer Center and University of Miami Miller School of Medicine, Miami, FL, 33136, USA. (18) Department of Surgery at Sylvester Comprehensive Cancer Center and University of Miami Miller School of Medicine, Miami, FL, 33136, USA. Electronic address: vikas.dudeja@med.miami.edu.

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Metabolic Symbiosis and Immunomodulation: How Tumor Cell-Derived Lactate May Disturb Innate and Adaptive Immune Responses

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The tumor microenvironment (TME) is composed by cellular and non-cellular components. Examples include the following: (i) bone marrow-derived inflammatory cells, (ii) fibroblasts, (iii) blood vessels, (iv) immune cells, and (v) extracellular matrix components. In most cases, this combination of components may result in an inhospitable environment, in which a significant retrenchment in nutrients and oxygen considerably disturbs cell metabolism. Cancer cells are characterized by an enhanced uptake and utilization of glucose, a phenomenon described by Otto Warburg over 90 years ago. One of the main products of this reprogrammed cell metabolism is lactate. "Lactagenic" or lactate-producing cancer cells are characterized by their immunomodulatory properties, since lactate, the end product of the aerobic glycolysis, besides acting as an inducer of cellular signaling phenomena to influence cellular fate, might also play a role as an immunosuppressive metabolite. Over the last 10 years, it has been well accepted that in the TME, the lactate secreted by transformed cells is able to compromise the function and/or assembly of an effective immune response against tumors. Herein, we will discuss recent advances regarding the deleterious effect of high concentrations of lactate on the tumor-infiltrating immune cells, which might characterize an innovative way of understanding the tumor-immune privilege.

Author Info: (1) Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. Laboratorio de Imunoparasitologia, Instituto Oswaldo Cruz, Fundacao Oswaldo Cruz (Fiocruz), Rio

Author Info: (1) Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. Laboratorio de Imunoparasitologia, Instituto Oswaldo Cruz, Fundacao Oswaldo Cruz (Fiocruz), Rio de Janeiro, Brazil. (2) Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. (3) Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. (4) Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. (5) Instituto de Microbiologia, Departamento de Imunologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. (6) Instituto de Microbiologia, Departamento de Imunologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. (7) Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. (8) Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. (9) Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. (10) Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.

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