Journal Articles

Metabolism and Microbiota

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

SIRT1 and HIF1alpha signaling in metabolism and immune responses

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SIRT1 and HIF1alpha are regarded as two key metabolic sensors in cellular metabolism pathways and play vital roles in influencing immune responses. SIRT1 and HIF1alpha regulate immune responses in metabolism-dependent and -independent ways. Here, we summarized the recent knowledge of SIRT1 and HIF1alpha signaling in metabolism and immune responses. HIF1alpha is a direct target of SIRT1. Sometimes, SIRT1 and HIF1alpha cooperate or act separately to mediate immune responses. In innate immune responses, SIRT1 can regulate the glycolytic activity of myeloid-derived suppressor cells (MDSCs) and influence MDSC functional differentiation. SIRT1 can regulate monocyte function through NF-kappaB and PGC-1, accompanying an increased NAD(+) level. The SIRT1-HIF1alpha axis bridges the innate immune signal to an adaptive immune response by directing cytokine production of dendritic cells in a metabolism-independent manner, promoting the differentiation of CD4(+) T cells. For adaptive immune cells, SIRT1 can mediate the differentiation of inflammatory T cell subsets in a NAD(+)-dependent manner. HIF1alpha can stimulate some glycolysis-associated genes and regulate the ATP and ROS generations. In addition, SIRT1-and HIF1alpha-associated metabolism inhibits the activity of mTOR, thus negatively regulating the differentiation and function of Th9 cells. As immune cells are crucial in controlling immune-associated diseases, SIRT1-and HIF1alpha associated-metabolism is closely linked to immune-associated diseases, including infection, tumors, allergic airway inflammation, and autoimmune diseases.

Author Info: (1) Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing

Author Info: (1) Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing 100875 China. (2) Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing 100875 China. (3) Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing 100875 China. (4) Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing 100875 China. Electronic address: liugw@bnu.edu.cn.

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Translating Science into Survival: Report on the Third International Cancer Immunotherapy Conference

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On September 6 to 9, 2017, in Mainz, Germany, the Third International Cancer Immunotherapy Conference was hosted jointly by the Cancer Research Institute, the Association for Cancer Immunotherapy, the European Academy of Tumor Immunology, and the American Association for Cancer Research. For the third straight year, more than 1,400 people attended the four-day event, which covered the latest advances in cancer immunology and immunotherapy. This report provides an overview of the main topics discussed. Cancer Immunol Res; 6(1); 10-13. (c)2017 AACR.

Author Info: (1) TRON - Translational Oncology, University Medical Center of Johannes Gutenberg University, Mainz, Germany. (2) TRON - Translational Oncology, University Medical Center of Johannes Gutenberg

Author Info: (1) TRON - Translational Oncology, University Medical Center of Johannes Gutenberg University, Mainz, Germany. (2) TRON - Translational Oncology, University Medical Center of Johannes Gutenberg University, Mainz, Germany. (3) Cancer Research Institute, New York, New York. abrodsky@cancerresearch.org.

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Cholesterol Esterification Enzyme Inhibition Enhances Antitumor Effects of Human Chimeric Antigen Receptors Modified T Cells

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Chimeric antigen receptor-modified T cell (CART) therapy has been demonstrated to have significant effect on hematologic tumor in patients. However, many persistent obstacles and challenges still limit the application. It is known that CD8 T cells are a key component of antitumor immunity. An avasimibe-induced inhibition of cholesterol esterification has been shown to improve the antitumor response of CD8 T cells in mice. In this study, using human CD19-directed CART cells as effector cells and CD19-overexpressing K562 cells as target cells, we detected whether cholesterol acyltransferase inhibition by avasimibe can enhance the antitumor effect of human CART cells. After avasimibe treatment, the infection rate was dropped by up to 50% (P<0.05). The cytotoxic effect of CART cells was significantly increased than the control group in a dose-dependent manner. Moreover, the level of secreted interferon-gamma increased in almost half of the cases (P<0.05); the ratio of CD8CD4 T cells was increased among the total T cells and the CART cells in some of cases (P<0.05). Our study suggests that inhibition of cholesterol acyltransferase can promote the antitumor effect of CART cells, and provides a new option for a combination therapy by regulating T-cell metabolism to enhance antitumor effects.

Author Info: (1) Oncological and Endoscopic Surgery Department. (2) Oncological and Endoscopic Surgery Department. (3) Oncological and Endoscopic Surgery Department. (4) College of Chemistry and Molecular Engineering

Author Info: (1) Oncological and Endoscopic Surgery Department. (2) Oncological and Endoscopic Surgery Department. (3) Oncological and Endoscopic Surgery Department. (4) College of Chemistry and Molecular Engineering, East China Normal University. (5) Oncological and Endoscopic Surgery Department. (6) Oncological and Endoscopic Surgery Department. (7) Oncological and Endoscopic Surgery Department. (8) Oncological and Endoscopic Surgery Department. (9) Oncological and Endoscopic Surgery Department. (10) Oncological and Endoscopic Surgery Department. (11) Oncological and Endoscopic Surgery Department. (12) College of Chemistry and Molecular Engineering, East China Normal University. (13) Oncological and Endoscopic Surgery Department. Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences. (14) Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences. Hematology Department, First Hospital of Harbin Medical University.

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A2AR adenosine signaling suppresses natural killer cell maturation in the tumor microenvironment

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Extracellular adenosine is a key immunosuppressive metabolite that restricts activation of cytotoxic lymphocytes and impairs anti-tumor immune responses. Here, we show that engagement of A2A adenosine receptor (A2AR) acts as a checkpoint that limits the maturation of natural killer (NK) cells. Both global and NK cell-specific conditional deletion of A2AR enhanced proportions of terminally mature NK cells at homeostasis, following reconstitution, and in the tumor microenvironment. Notably, A2AR-deficient, terminally mature NK cells retained proliferative capacity and exhibited heightened reconstitution in competitive transfer assays. Moreover, targeting A2AR specifically on NK cells also improved tumor control and delayed tumor initiation. Taken together, our results establish A2AR-mediated adenosine signaling as an intrinsic negative regulator of NK cell maturation and anti-tumor immune responses. On the basis of these findings, we propose that administering A2AR antagonists concurrently with NK cell-based therapies may heighten therapeutic benefits by augmenting NK cell-mediated anti-tumor immunity.

Author Info: (1) Diabetes Center, University of California, San Francisco. (2) Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute. (3) Immunology in Cancer and

Author Info: (1) Diabetes Center, University of California, San Francisco. (2) Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute. (3) Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute. (4) Department of Medical Genomics, QIMR Berghofer Medical Research Institute. (5) Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute. (6) Institut Gustave Roussy, INSERM. (7) La Jolla Institute For Allergy & Immunology. (8) Institute for Immunology and Infectious Diseases, Murdoch University. (9) Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute. (10) INSERM-CIC Institut Gustave Roussy. (11) Lions Eye Institute, Centre for Experimental Immunology. (12) CNRS, INSERM, CIML, Aix Marseille University. (13) Medical Genomics Laboratory, QIMR Berghofer Medical Research Institute. (14) Developmental Immunology, La Jolla Institute for Allergy and Immunology. (15) Molecular Immunolgy, WEHI. (16) Molecular Immunology, Walter and Elisa Hall Institute. (17) Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute mark.smyth@qimrberghofer.edu.au.

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Convergence of Cancer Metabolism and Immunity: an Overview

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Cancer metabolism as a field of research was founded almost 100 years ago by Otto Warburg, who described the propensity for cancers to convert glucose to lactate despite the presence of oxygen, which in yeast diminishes glycolytic metabolism known as the Pasteur effect. In the past 20 years, the resurgence of interest in cancer metabolism provided significant insights into processes involved in maintenance metabolism of non-proliferating cells and proliferative metabolism, which is regulated by proto-oncogenes and tumor suppressors in normal proliferating cells. In cancer cells, depending on the driving oncogenic event, metabolism is re-wired for nutrient import, redox homeostasis, protein quality control, and biosynthesis to support cell growth and division. In general, resting cells rely on oxidative metabolism, while proliferating cells rewire metabolism toward glycolysis, which favors many biosynthetic pathways for proliferation. Oncogenes such as MYC, BRAF, KRAS, and PI3K have been documented to rewire metabolism in favor of proliferation. These cell intrinsic mechanisms, however, are insufficient to drive tumorigenesis because immune surveillance continuously seeks to destroy neo-antigenic tumor cells. In this regard, evasion of cancer cells from immunity involves checkpoints that blunt cytotoxic T cells, which are also attenuated by the metabolic tumor microenvironment, which is rich in immuno-modulating metabolites such as lactate, 2-hydroxyglutarate, kyneurenine, and the proton (low pH). As such, a full understanding of tumor metabolism requires an appreciation of the convergence of cancer cell intrinsic metabolism and that of the tumor microenvironment including stromal and immune cells.

Author Info: (1) Ludwig Institute for Cancer Research, New York, NY 10017, USA. The Wistar Institute, Philadelphia, PA 19104, USA. (2) Department of Biological Sciences, The University

Author Info: (1) Ludwig Institute for Cancer Research, New York, NY 10017, USA. The Wistar Institute, Philadelphia, PA 19104, USA. (2) Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX 75080, USA.

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An Overview of l-Amino Acid Oxidase Functions from Bacteria to Mammals: Focus on the Immunoregulatory Phenylalanine Oxidase IL4I1

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l-amino acid oxidases are flavin adenine dinucleotide-dependent enzymes present in all major kingdom of life, from bacteria to mammals. They participate in defense mechanisms by limiting the growth of most bacteria and parasites. A few mammalian LAAOs have been described, of which the enzyme "interleukin-4 induced gene 1" (IL4I1) is the best characterized. IL4I1 mainly oxidizes l-phenylalanine. It is a secreted enzyme physiologically produced by antigen presenting cells of the myeloid and B cell lineages and T helper type (Th) 17 cells. Important roles of IL4I1 in the fine control of the adaptive immune response in mice and humans have emerged during the last few years. Indeed, IL4I1 inhibits T cell proliferation and cytokine production and facilitates naive CD4(+) T-cell differentiation into regulatory T cells in vitro by limiting the capacity of T lymphocytes to respond to clonal receptor stimulation. It may also play a role in controlling the germinal center reaction for antibody production and limiting Th1 and Th17 responses. IL4I1 is expressed in tumor-associated macrophages of most human cancers and in some tumor cell types. Such expression, associated with its capacity to facilitate tumor growth by inhibiting the anti-tumor T-cell response, makes IL4I1 a new potential druggable target in the field of immunomodulation in cancer.

Author Info: (1) The Mondor Institute of Biomedical Research (IMRB), INSERM U955, Team 09, F-94010 Creteil CEDEX, France. valerie.frenkel@inserm.fr. Faculty of Medicine, Paris Est University, F-94010 Creteil

Author Info: (1) The Mondor Institute of Biomedical Research (IMRB), INSERM U955, Team 09, F-94010 Creteil CEDEX, France. valerie.frenkel@inserm.fr. Faculty of Medicine, Paris Est University, F-94010 Creteil CEDEX, France. valerie.frenkel@inserm.fr. Biological Resources Platform, Henri Mondor Hospital, AP-HP, F-94010 Creteil, France. valerie.frenkel@inserm.fr. (2) The Mondor Institute of Biomedical Research (IMRB), INSERM U955, Team 09, F-94010 Creteil CEDEX, France. flavia.castellano@inserm.fr. Faculty of Medicine, Paris Est University, F-94010 Creteil CEDEX, France. flavia.castellano@inserm.fr. Department of Hematology-Immunology, Henri Mondor Hospital, AP-HP, F-94010 Creteil, France. flavia.castellano@inserm.fr.

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CD38-NAD+Axis Regulates Immunotherapeutic Anti-Tumor T Cell Response

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Heightened effector function and prolonged persistence, the key attributes of Th1 and Th17 cells, respectively, are key features of potent anti-tumor T cells. Here, we established ex vivo culture conditions to generate hybrid Th1/17 cells, which persisted long-term in vivo while maintaining their effector function. Using transcriptomics and metabolic profiling approaches, we showed that the enhanced anti-tumor property of Th1/17 cells was dependent on the increased NAD+-dependent activity of the histone deacetylase Sirt1. Pharmacological or genetic inhibition of Sirt1 activity impaired the anti-tumor potential of Th1/17 cells. Importantly, T cells with reduced surface expression of the NADase CD38 exhibited intrinsically higher NAD+, enhanced oxidative phosphorylation, higher glutaminolysis, and altered mitochondrial dynamics that vastly improved tumor control. Lastly, blocking CD38 expression improved tumor control even when using Th0 anti-tumor T cells. Thus, strategies targeting the CD38-NAD+ axis could increase the efficacy of anti-tumor adoptive T cell therapy.

Author Info: (1) Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. (2) Department of Microbiology and Immunology, Hollings Cancer Center

Author Info: (1) Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. (2) Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. (3) Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. (4) Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. (5) Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. (6) Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. (7) Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. (8) Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. (9) Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. (10) Department of Pathology and Laboratory Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. (11) Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. (12) Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. (13) Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. (14) Department of Pharmaceutical and Biomedical Sciences, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. (15) Department of Pharmaceutical and Biomedical Sciences, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. (16) Department of Pathology and Laboratory Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. (17) Department of Ophthalmology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. (18) Department of Public Health, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. (19) Department of Nephrology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. (20) Department of Pathology and Laboratory Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. (21) Department of Surgery, Loyola University, Maywood, IL 60153, USA. (22) Department of Pharmaceutical and Biomedical Sciences, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. (23) Randolph-Macon College, Ashland, VA 23005, USA. (24) Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. (25) Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. (26) Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. (27) Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN 37232, USA. (28) Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. (29) Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. Electronic address: mehrotr@musc.edu.

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Suppression of FIP200 and autophagy by tumor-derived lactate promotes naive T cell apoptosis and affects tumor immunity

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Xia et al. made the seminal observation that naive T cells from blood and tumor tissue of ovarian cancer patients and tumor-bearing mice were prone to apoptosis. They traced the cause to tumor-derived lactate, which translationally inhibits the expression of FIP200, a protein required for autophagy, leading to impaired autophagy induction, overactivated mitochondria, high levels of reactive oxygen species, and disruption of Bcl-2 gene family expression.

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Xia et al. made the seminal observation that naive T cells from blood and tumor tissue of ovarian cancer patients and tumor-bearing mice were prone to apoptosis. They traced the cause to tumor-derived lactate, which translationally inhibits the expression of FIP200, a protein required for autophagy, leading to impaired autophagy induction, overactivated mitochondria, high levels of reactive oxygen species, and disruption of Bcl-2 gene family expression.

Naive T cells are poorly studied in cancer patients. We report that naive T cells are prone to undergo apoptosis due to a selective loss of FAK family-interacting protein of 200 kDa (FIP200) in ovarian cancer patients and tumor-bearing mice. This results in poor antitumor immunity via autophagy deficiency, mitochondria overactivation, and high reactive oxygen species production in T cells. Mechanistically, loss of FIP200 disables the balance between proapoptotic and antiapoptotic Bcl-2 family members via enhanced argonaute 2 (Ago2) degradation, reduced Ago2 and microRNA1198-5p complex formation, less microRNA1198-5p maturation, and consequently abolished microRNA1198-5p-mediated repression on apoptotic gene Bak1 Bcl-2 overexpression and mitochondria complex I inhibition rescue T cell apoptosis and promoted tumor immunity. Tumor-derived lactate translationally inhibits FIP200 expression by down-regulating the nicotinamide adenine dinucleotide level while potentially up-regulating the inhibitory effect of adenylate-uridylate-rich elements within the 3' untranslated region of Fip200 mRNA. Thus, tumors metabolically target naive T cells to evade immunity.

Author Info: (1) Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA. (2) Department of Surgery, University of Michigan School of Medicine

Author Info: (1) Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA. (2) Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA. Department of Immunology and Key Laboratory of Medical Immunology of Ministry of Public Health, Peking University Health Science Center, Beijing 100191, China. (3) Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA. Graduate Program in Immunology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA. (4) Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA. Graduate Program in Immunology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA. (5) Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA. (6) Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA. (7) Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA. Department of Environmental Health, Cincinnati University College of Medicine, Cincinnati, OH 45267, USA. (8) Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA. (9) Department of Immunology, School of Medicine, Duke University, Durham, NC 27710, USA. (10) Department of Obstetrics and Gynecology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA. (11) Department of Immunology, School of Medicine, Duke University, Durham, NC 27710, USA. (12) Department of Women's Health Services, Henry Ford Health System, Detroit, MI 48202, USA. (13) Department of Women's Health Services, Henry Ford Health System, Detroit, MI 48202, USA. (14) Department of Cancer Biology, Cincinnati University College of Medicine, Cincinnati, OH 45267, USA. (15) Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA. wzou@med.umich.edu. Graduate Program in Immunology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA. Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA. Graduate Program in Tumor Biology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA. University of Michigan Comprehensive Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.

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Targeting immuno-metabolism to improve anti-cancer therapies

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The immunology community has made significant strides in recent years in using the immune system to target and eliminate cancer. Therapies such as hematopoietic stem cell transplantation (HSCT) are the standard of care treatment for several malignancies, while therapies incorporating chimeric antigen receptor (CAR) T cells or checkpoint molecule blockade have been revolutionary. However, these approaches are not optimal for all cancers and in some cases, have failed outright. The greatest obstacle to making these therapies more effective may be rooted in one of the most basic concepts of cell biology, metabolism. Research over the last decade has revealed that T cell proliferation and differentiation is intimately linked to robust changes in metabolic activity, delineation of which may provide ways to manipulate the immuno-oncologic responses to our advantage. Here, we provide a basic overview of T cell metabolism, discuss what is known about metabolic regulation of T cells during allogeneic HSCT, point to evidence on the importance of T cell metabolism during CAR T cell and solid tumor therapies, and speculate about the role for compounds that might have dual-action on both immune cells and tumor cells simultaneously.

Author Info: (1) Division of Blood and Marrow Transplant and Cellular Therapies, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA. (2) Division

Author Info: (1) Division of Blood and Marrow Transplant and Cellular Therapies, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA. (2) Division of Blood and Marrow Transplant and Cellular Therapies, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA. Electronic address: craig.byersdorfer@chp.edu.

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Butyrate and propionate inhibit antigen-specific CD8+ T cell activation by suppressing IL-12 production by antigen-presenting cells

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Short chain fatty acids (SCFAs), such as acetate, butyrate and propionate, are products of microbial macronutrients fermentation that distribute systemically and are believed to modulate host immune responses. Recent data have indicated that certain SCFAs, such as butyrate and propionate, directly modulate human dendritic cell (DC) function. Given the role of DCs in initiating and shaping the adaptive immune response, we now explore how SCFAs affect the activation of antigen-specific CD8+ T cells stimulated with autologous, MART1 peptide-pulsed DC. We show that butyrate reduces the frequency of peptide-specific CD8+ T cells and, together with propionate, inhibit the activity of those cells. On the contrary, acetate does not affect them. Importantly, butyrate and propionate inhibit the production of IL-12 and IL-23 in the DCs and exogenous IL-12 fully restores the activation of the MART-1-specific CD8+ T cells, whereas IL-23 has no effect. In conclusion, these results point to a pivotal role of butyrate and propionate in modulating CD8+ T cell activation via the inhibition of IL-12 secretion from DCs. These findings reveal a novel mechanism whereby bacterial fermentation products may modulate CD8+ T cell function with possible implications in anti-cancer immunotherapy.

Author Info: (1) Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark. (2) Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark. (3) Department of

Author Info: (1) Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark. (2) Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark. (3) Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark. (4) Center for Cancer Immune Therapy (CCIT), Department of Hematology, Copenhagen University Hospital, Herlev, Denmark. (5) Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark. (6) Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark. (7) Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark. Center for Cancer Immune Therapy (CCIT), Department of Hematology, Copenhagen University Hospital, Herlev, Denmark. (8) Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark. (9) Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark. awoetmann@sund.ku.dk.

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