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      Impact of Metabolism on T-Cell Differentiation and Function and Cross Talk with Tumor Microenvironment

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          Abstract

          The immune system and metabolism are highly integrated and multilevel interactions between metabolic system and T lymphocyte signaling and fate exist. Accumulating evidence indicates that the regulation of nutrient uptake and utilization in T cells is critically important for the control of their differentiation and manipulating metabolic pathways in these cells can shape their function and survival. This review will discuss some potential cell metabolism pathways involved in shaping T lymphocyte function and differentiation. It will also describe show subsets of T cells have specific metabolic requirements and signaling pathways that contribute to their respective function. Examples showing the apparent similarity between cancer cell metabolism and T cells during activation are illustrated and finally some mechanisms being used by tumor microenvironment to orchestrate T-cell metabolic dysregulation and the subsequent emergence of immune suppression are discussed. We believe that targeting T-cell metabolism may provide an additional opportunity to manipulate T-cell function in the development of novel therapeutics.

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          Most cited references109

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          The blockade of immune checkpoints in cancer immunotherapy.

          Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
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            Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells.

            Although immune mechanisms can suppress tumour growth, tumours establish potent, overlapping mechanisms that mediate immune evasion. Emerging evidence suggests a link between angiogenesis and the tolerance of tumours to immune mechanisms. Hypoxia, a condition that is known to drive angiogenesis in tumours, results in the release of damage-associated pattern molecules, which can trigger the rejection of tumours by the immune system. Thus, the counter-activation of tolerance mechanisms at the site of tumour hypoxia would be a crucial condition for maintaining the immunological escape of tumours. However, a direct link between tumour hypoxia and tolerance through the recruitment of regulatory cells has not been established. We proposed that tumour hypoxia induces the expression of chemotactic factors that promote tolerance. Here we show that tumour hypoxia promotes the recruitment of regulatory T (T(reg)) cells through induction of expression of the chemokine CC-chemokine ligand 28 (CCL28), which, in turn, promotes tumour tolerance and angiogenesis. Thus, peripheral immune tolerance and angiogenesis programs are closely connected and cooperate to sustain tumour growth. ©2011 Macmillan Publishers Limited. All rights reserved
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              IDO expression by dendritic cells: tolerance and tryptophan catabolism.

              Indoleamine 2,3-dioxygenase (IDO) is an enzyme that degrades the essential amino acid tryptophan. The concept that cells expressing IDO can suppress T-cell responses and promote tolerance is a relatively new paradigm in immunology. Considerable evidence now supports this hypothesis, including studies of mammalian pregnancy, tumour resistance, chronic infections and autoimmune diseases. In this review, we summarize key recent developments and propose a unifying model for the role of IDO in tolerance induction.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                13 March 2017
                2017
                : 8
                : 270
                Affiliations
                [1] 1ISBST, Laboratory BVBGR, LR11ES31, Higher Institute of Biotechnology of Sidi Thabet, University of Manouba , Sidi Thabet, Tunisia
                [2] 2Laboratory of Genetics, Immunology and Human Pathology, Faculty of Sciences of Tunis, University Tunis El Manar , Tunis, Tunisia
                [3] 3Institut National de la Santé et de la Recherche Médicale (INSERM) UMR1186, Laboratory «Integrative Tumor Immunology and Genetic Oncology», Equipe Labellisée LIGUE 2015 , Villejuif, France
                [4] 4Institut National de la Santé et de la Recherche Médicale (INSERM), Gustave Roussy, University of Paris-Sud , Villejuif, France
                [5] 5Institut National de la Santé et de la Recherche Médicale (INSERM), Gustave Roussy, Université Paris-Saclay , Villejuif, France
                Author notes

                Edited by: Yongsheng Li, Third Military Medical University, China

                Reviewed by: Bruno Silva-Santos, Universidade de Lisboa, Portugal; Kankana Bardhan, Massachusetts General Hospital, USA; Luca Gattinoni, National Cancer Institute, USA; Zong Sheng Guo, Harvard University, USA

                *Correspondence: Salem Chouaib, salem.chouaib@ 123456gustaveroussy.fr

                Specialty section: This article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2017.00270
                5346542
                28348562
                a80da9a1-5361-45f4-9b3c-8b6a2924e1ea
                Copyright © 2017 Kouidhi, Elgaaied and Chouaib.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 15 November 2016
                : 24 February 2017
                Page count
                Figures: 1, Tables: 0, Equations: 0, References: 188, Pages: 13, Words: 11474
                Categories
                Immunology
                Review

                Immunology
                immune system,t-lymphocytes,tumor cell metabolism,cancer,hypoxia,tumor microenvironment
                Immunology
                immune system, t-lymphocytes, tumor cell metabolism, cancer, hypoxia, tumor microenvironment

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