Journal Articles

Metabolism and Microbiota

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

Glycolytic metabolism is essential for CCR7 oligomerization and dendritic cell migration

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Dendritic cells (DCs) are first responders of the innate immune system that integrate signals from external stimuli to direct context-specific immune responses. Current models suggest that an active switch from mitochondrial metabolism to glycolysis accompanies DC activation to support the anabolic requirements of DC function. We show that early glycolytic activation is a common program for both strong and weak stimuli, but that weakly activated DCs lack long-term HIF-1alpha-dependent glycolytic reprogramming and retain mitochondrial oxidative metabolism. Early induction of glycolysis is associated with activation of AKT, TBK, and mTOR, and sustained activation of these pathways is associated with long-term glycolytic reprogramming. We show that inhibition of glycolysis impaired maintenance of elongated cell shape, DC motility, CCR7 oligomerization, and DC migration to draining lymph nodes. Together, our results indicate that early induction of glycolysis occurs independent of pro-inflammatory phenotype, and that glycolysis supports DC migratory ability regardless of mitochondrial bioenergetics.

Author Info: (1) Goodman Cancer Research Centre, Department of Physiology, McGill University, Montreal, QC, H3G 1Y6, Canada. (2) Goodman Cancer Research Centre, Department of Oncology, McGill University

Author Info: (1) Goodman Cancer Research Centre, Department of Physiology, McGill University, Montreal, QC, H3G 1Y6, Canada. (2) Goodman Cancer Research Centre, Department of Oncology, McGill University, Montreal, QC, H3G 1Y6, Canada. (3) Goodman Cancer Research Centre, Department of Physiology, McGill University, Montreal, QC, H3G 1Y6, Canada. (4) Meakins-Christie Laboratories, Research Institute of McGill University Health Center, Department of Medicine, McGill University, Montreal, H4A 3J1, QC, Canada. Goodman Cancer Research Centre, Department of Microbiology and Immunology, McGill University, Montreal, QC, H3G 1Y6, Canada. (5) Goodman Cancer Research Centre, Department of Oncology, McGill University, Montreal, QC, H3G 1Y6, Canada. (6) Goodman Cancer Research Centre, Department of Physiology, McGill University, Montreal, QC, H3G 1Y6, Canada. (7) Goodman Cancer Research Centre, Department of Microbiology and Immunology, McGill University, Montreal, QC, H3G 1Y6, Canada. (8) Meakins-Christie Laboratories, Research Institute of McGill University Health Center, Department of Medicine, McGill University, Montreal, H4A 3J1, QC, Canada. (9) Goodman Cancer Research Centre, Department of Physiology, McGill University, Montreal, QC, H3G 1Y6, Canada. (10) Goodman Cancer Research Centre, Department of Oncology, McGill University, Montreal, QC, H3G 1Y6, Canada. (11) Goodman Cancer Research Centre, Department of Physiology, McGill University, Montreal, QC, H3G 1Y6, Canada. connie.krawczyk@mcgill.ca. Goodman Cancer Research Centre, Department of Microbiology and Immunology, McGill University, Montreal, QC, H3G 1Y6, Canada. connie.krawczyk@mcgill.ca.

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Fatty acid metabolism complements glycolysis in the selective regulatory T cell expansion during tumor growth

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The tumor microenvironment restrains conventional T cell (Tconv) activation while facilitating the expansion of Tregs. Here we showed that Tregs' advantage in the tumor milieu relies on supplemental energetic routes involving lipid metabolism. In murine models, tumor-infiltrating Tregs displayed intracellular lipid accumulation, which was attributable to an increased rate of fatty acid (FA) synthesis. Since the relative advantage in glucose uptake may fuel FA synthesis in intratumoral Tregs, we demonstrated that both glycolytic and oxidative metabolism contribute to Tregs' expansion. We corroborated our data in human tumors showing that Tregs displayed a gene signature oriented toward glycolysis and lipid synthesis. Our data support a model in which signals from the tumor microenvironment induce a circuitry of glycolysis, FA synthesis, and oxidation that confers a preferential proliferative advantage to Tregs, whose targeting might represent a strategy for cancer treatment.

Author Info: (1) Dipartimento di Medicina Interna e Specialita Mediche, Sapienza Universita di Roma, 00161 Rome, Italy. (2) Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale

Author Info: (1) Dipartimento di Medicina Interna e Specialita Mediche, Sapienza Universita di Roma, 00161 Rome, Italy. (2) Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche, 80131 Naples, Italy. (3) Dipartimento di Medicina Interna e Specialita Mediche, Sapienza Universita di Roma, 00161 Rome, Italy. (4) Dipartimento di Medicina Interna e Specialita Mediche, Sapienza Universita di Roma, 00161 Rome, Italy. (5) Dipartimento di Medicina Interna e Specialita Mediche, Sapienza Universita di Roma, 00161 Rome, Italy. (6) Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche, 80131 Naples, Italy. (7) Department of Infectious Diseases, Istituto Superiore di Sanita, 00161 Rome, Italy. (8) Department of Infectious Diseases, Istituto Superiore di Sanita, 00161 Rome, Italy. (9) Department of Infectious Diseases, Istituto Superiore di Sanita, 00161 Rome, Italy. (10) Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, 20122 Milan, Italy. (11) Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, 20122 Milan, Italy. (12) Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, 20122 Milan, Italy. Curtin Health Innovation Research Institute, School of Pharmacy and Biomedical Sciences, Curtin University, Perth, WA 6102, Australia. (13) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, 20122 Milan, Italy. (14) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, 20122 Milan, Italy. (15) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, 20122 Milan, Italy. Department of Medical Biotechnology and Translational Medicine, Universita degli Studi di Milano, 20133 Milan, Italy. (16) Immunology Research Area, Ospedale Pediatrico Bambino Gesu Istituto di Ricovero e Cura a Carattere Scientifico, 00146 Rome, Italy. (17) Laboratoire de Pathogenese des Virus de l'Hepatite B, Institut Pasteur, 75015 Paris, France. (18) Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche, 80131 Naples, Italy; giuseppe.matarese@unina.it vincenzo.barnaba@uniroma1.it silvia.piconese@uniroma1.it. Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universita di Napoli Federico II, 80131 Naples, Italy. (19) Dipartimento di Medicina Interna e Specialita Mediche, Sapienza Universita di Roma, 00161 Rome, Italy; giuseppe.matarese@unina.it vincenzo.barnaba@uniroma1.it silvia.piconese@uniroma1.it. Istituto Pasteur Italia-Fondazione Cenci Bolognetti, 00161 Rome, Italy. Center for Life Nano Science, Istituto Italiano di Tecnologia, 00161 Rome, Italy. (20) Dipartimento di Medicina Interna e Specialita Mediche, Sapienza Universita di Roma, 00161 Rome, Italy; giuseppe.matarese@unina.it vincenzo.barnaba@uniroma1.it silvia.piconese@uniroma1.it. Istituto Pasteur Italia-Fondazione Cenci Bolognetti, 00161 Rome, Italy.

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Inhibition of the adenosine A2a receptor modulates expression of T cell coinhibitory receptors and improves effector function for enhanced checkpoint blockade and ACT in murine cancer models

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Adenosine signaling via the A2a receptor (A2aR) is emerging as an important checkpoint of immune responses. The presence of adenosine in the inflammatory milieu or generated by the CD39/CD73 axis on tissues or T regulatory cells serves to regulate immune responses. By nature of the specialized metabolism of cancer cells, adenosine levels are increased in the tumor microenvironment and contribute to tumor immune evasion. To this end, small molecule inhibitors of the A2aR are being pursued clinically to enhance immunotherapy. Herein, we demonstrate the ability of the novel A2aR antagonist, CPI-444, to dramatically enhance immunologic responses in models of checkpoint therapy and ACT in cancer. Furthermore, we demonstrate that A2aR blockade with CPI-444 decreases expression of multiple checkpoint pathways, including PD-1 and LAG-3, on both CD8+ effector T cells (Teff) and FoxP3+ CD4+ regulatory T cells (Tregs). Interestingly, our studies demonstrate that A2aR blockade likely has its most profound effects during Teff cell activation, significantly decreasing PD-1 and LAG-3 expression at the draining lymph nodes of tumor bearing mice. In contrast to previous reports using A2aR knockout models, pharmacologic blockade with CPI-444 did not impede CD8 T cell persistence or memory recall. Overall these findings not only redefine our understanding of the mechanisms by which adenosine inhibits immunity but also have important implications for the design of novel immunotherapy regimens.

Author Info: (1) Department of Oncology, Sidney-Kimmel Comprehensive Cancer Research Center, Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA. (2)

Author Info: (1) Department of Oncology, Sidney-Kimmel Comprehensive Cancer Research Center, Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA. (2) Department of Oncology, Sidney-Kimmel Comprehensive Cancer Research Center, Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA. (3) Department of Oncology, Sidney-Kimmel Comprehensive Cancer Research Center, Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA. (4) Department of Oncology, Sidney-Kimmel Comprehensive Cancer Research Center, Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA. (5) Department of Oncology, Sidney-Kimmel Comprehensive Cancer Research Center, Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA. (6) Department of Oncology, Sidney-Kimmel Comprehensive Cancer Research Center, Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA. MedImmune, LLC, Gaithersburg, MD, 20878, USA. (7) Department of Oncology, Sidney-Kimmel Comprehensive Cancer Research Center, Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, 1650 Orleans Street, CRB1 Room 453, Baltimore, MD, 21231, USA. poweljo@jhmi.edu.

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D-2-hydroxyglutarate interferes with HIF-1alpha stability skewing T-cell metabolism towards oxidative phosphorylation and impairing Th17 polarization

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D-2-hydroxyglutarate (D-2HG) is released by various types of malignant cells including acute myeloid leukemia (AML) blasts carrying isocitrate dehydrogenase (IDH) gain-of-function mutations. D-2HG acting as an oncometabolite promotes proliferation, anoikis, and differentiation block of hematopoietic cells in an autocrine fashion. However, prognostic impact of IDH mutations and high D-2HG levels remains controversial and might depend on the overall mutational context. An increasing number of studies focus on the permissive environment created by AML blasts to promote immune evasion. Impact of D-2HG on immune cells remains incompletely understood. Here, we sought out to investigate the effects of D-2HG on T-cells as key mediators of anti-AML immunity. D-2HG was efficiently taken up by T-cells in vitro, which is in line with high 2-HG levels measured in T-cells isolated from AML patients carrying IDH mutations. T-cell activation was slightly impacted by D-2HG. However, D-2HG triggered HIF-1a protein destabilization resulting in metabolic skewing towards oxidative phosphorylation, increased regulatory T-cell (Treg) frequency, and reduced T helper 17 (Th17) polarization. Our data suggest for the first time that D-2HG might contribute to fine tuning of immune responses.

Author Info: (1) Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany. (2) Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, Regensburg

Author Info: (1) Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany. (2) Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, Regensburg, Germany. (3) Institute of Functional Genomics, University of Regensburg, Regensburg, Germany. (4) Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany. (5) Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, Regensburg, Germany. (6) Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, Regensburg, Germany. (7) Institute of Functional Genomics, University of Regensburg, Regensburg, Germany. (8) Institute of Functional Genomics, University of Regensburg, Regensburg, Germany. (9) Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany. (10) Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, Regensburg, Germany. (11) Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany.

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Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells

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Linking the microbiome and the immune response to primary tumors and metastases in the liver, Ma et al. found that when gram positive commensal bacteria (which metabolize primary bile acid to secondary bile acid) were depleted with antibiotics, the ratio of primary to secondary bile acids increased, causing liver sinusoidal endothelial cells to produce more of the chemokine CXCL16, which caused an accumulation of natural killer T (NKT) cells via the CXCR6 receptor. These NKT cells mediated an antitumor effect on primary tumors and metastases in the liver.

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Linking the microbiome and the immune response to primary tumors and metastases in the liver, Ma et al. found that when gram positive commensal bacteria (which metabolize primary bile acid to secondary bile acid) were depleted with antibiotics, the ratio of primary to secondary bile acids increased, causing liver sinusoidal endothelial cells to produce more of the chemokine CXCL16, which caused an accumulation of natural killer T (NKT) cells via the CXCR6 receptor. These NKT cells mediated an antitumor effect on primary tumors and metastases in the liver.

Primary liver tumors and liver metastasis currently represent the leading cause of cancer-related death. Commensal bacteria are important regulators of antitumor immunity, and although the liver is exposed to gut bacteria, their role in antitumor surveillance of liver tumors is poorly understood. We found that altering commensal gut bacteria in mice induced a liver-selective antitumor effect, with an increase of hepatic CXCR6(+) natural killer T (NKT) cells and heightened interferon-gamma production upon antigen stimulation. In vivo functional studies showed that NKT cells mediated liver-selective tumor inhibition. NKT cell accumulation was regulated by CXCL16 expression of liver sinusoidal endothelial cells, which was controlled by gut microbiome-mediated primary-to-secondary bile acid conversion. Our study suggests a link between gut bacteria-controlled bile acid metabolism and liver antitumor immunosurveillance.

Author Info: (1) Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (2)

Author Info: (1) Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (2) Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (3) Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (4) Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (5) Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (6) Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (7) Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (8) Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (9) Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (10) Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (11) Institute of Pathology, University Hospital RWTH Aachen, Aachen 52074, Germany. (12) Institute of Pathology, University Hospital RWTH Aachen, Aachen 52074, Germany. Institute of Pathology, University Hospital Heidelberg, Heidelberg 69120, Germany. (13) Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27607, USA. (14) Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (15) Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (16) Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Leidos Biomedical Research, Inc, Microbiome Sequencing Core, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (17) Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Leidos Biomedical Research, Inc, Microbiome Sequencing Core, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (18) Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Leidos Biomedical Research, Inc, Microbiome Sequencing Core, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (19) Chulabhorn Research Institute, Bangkok, Thailand. (20) Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (21) Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. NCI CCR Liver Cancer Program, Bethesda, MD, USA. (22) Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (23) Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. tim.greten@nih.gov. NCI CCR Liver Cancer Program, Bethesda, MD, USA.

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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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