1. Fatty acid metabolism complements glycolysis in the selective regulatory T cell expansion during tumor growth
- Author
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Giuseppe Matarese, Nico Mitro, Massimiliano Pagani, Martina Severa, Chiara Focaccetti, Yu Wei, Eliana M. Coccia, Stefano Miacci, Silvia Piconese, Eleonora Timperi, Claudio Procaccini, Giuseppe Danilo Norata, Ilenia Pacella, Valeria Ranzani, Vincenzo Barnaba, Fabiana Rizzo, Grazisa Rossetti, Fabrizia Bonacina, Ezio Giorda, Deriggio Faicchia, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Consiglio Nazionale delle Ricerche [Napoli] (CNR), Istituto Superiore di Sanità (ISS), Università degli Studi di Milano = University of Milan (UNIMI), Curtin University [Perth], Planning and Transport Research Centre (PATREC), Istituto Nazionale Genetica Molecolare [Milano] (INGM), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Pathogenèse des Virus de l'Hépatite B (PVHB), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Naples Federico II = Università degli studi di Napoli Federico II, Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP), Istituto Italiano di Tecnologia (IIT), This work was supported by Associazione Italiana per la Ricerca sul Cancro Grants IG-2014 15199 and IG-2017 19939 (to V.B.) and IG-2017 19784 (to S.P.), Ministry of Education, University and Research (MIUR) Grants RF-2010-2310438 and RF 2010-2318269, Fondazione Italiana Sclerosi Multipla Grants code 2015/R/04 (to V.B.), code 2013/R/9 (to E.M.C.), code 2016/R/18 (to G.M.), and code 2014/R/19 (to M.S.), MIUR Progetti di Ricerca di Interesse Nazionale Grant 2010-2011 protocol 2010LC747T_004, MIUR Fondo per gli Investimenti della Ricerca di Base 2011/13 Grant no. RBAP10TPXK, Istituto Pasteur Italia–Fondazione Cenci Bolognetti Grant 2014-2016, International Network Institut Pasteur Programmes Transversaux de Recherche Grant 20-16, Fondazione Roma Grant for Biomedical Research NCDS-2013-000000345, the European Union’s Seventh Framework Program (FP7) under Grant Agreement 259743 (MODHEP consortium) (to Y.W.), Fondazione Cariplo Grant 2016-0852 (to G.D.N.), Ministero della Salute Grants GR-2011-02346974 (to G.D.N.) and GR-2013-02355011 (to F.B.), and European Union IDEAS Programme European Research Council Starting Grant menTORingTregs 310496 and Telethon Grant GGP17086 (to G.M.). C.F. was supported by a 2015 Fellowship from Fondazione Veronesi., European Project: 259743,EC:FP7:HEALTH,FP7-HEALTH-2010-two-stage,MODHEP(2011), European Project: 310496,EC:FP7:ERC,ERC-2012-StG_20111109,MENTORINGTREGS(2013), Pacella, Ilenia, Procaccini, Claudio, Focaccetti, Chiara, Miacci, Stefano, Timperi, Eleonora, Faicchia, Deriggio, Severa, Martina, Rizzo, Fabiana, Coccia, Eliana Marina, Bonacina, Fabrizia, Mitro, Nico, Norata, Giuseppe Danilo, Rossetti, Grazisa, Ranzani, Valeria, Pagani, Massimiliano, Giorda, Ezio, Wei, Yu, Matarese, Giuseppe, Barnaba, Vincenzo, Piconese, Silvia, Istituto Superiore di Sanita [Rome], Systems biology of liver cancer: an integrative genomic-epigenomic approach - MODHEP - - EC:FP7:HEALTH2011-01-01 - 2016-06-30 - 259743 - VALID, Unravelling paradoxes in regulatory T cell biology: the molecular basis for an mTOR-dependent oscillatory metabolic switch controlling immune tolerance and autoimmunity - MENTORINGTREGS - - EC:FP7:ERC2013-05-01 - 2018-04-30 - 310496 - VALID, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Università degli Studi di Milano [Milano] (UNIMI), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Università degli studi di Napoli Federico II
- Subjects
0301 basic medicine ,MESH: Neoplasm Proteins ,MESH: Oxidation-Reduction ,Treg ,fatty acid synthesis ,glycolysis ,ox40 ,tumor microenvironment ,Glycolysi ,T-Lymphocytes ,Type I ,Settore MED/04 ,T-Lymphocytes, Regulatory ,Transgenic ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Neoplasms ,MESH: Tumor Microenvironment ,Glycolysis ,MESH: Animals ,Tumor ,Multidisciplinary ,Chemistry ,Fatty Acids ,hemic and immune systems ,Regulatory ,Cell biology ,Neoplasm Proteins ,MESH: Fatty Acids ,Fatty Acid Synthase, Type I ,medicine.anatomical_structure ,MESH: Neoplasms, Experimental ,PNAS Plus ,Fatty Acid Synthase ,030220 oncology & carcinogenesis ,MESH: Glycolysis ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,MESH: Fatty Acid Synthase, Type I ,Fatty acid synthesis ,Ox40 ,Tumor microenvironment ,Animals ,Cell Line, Tumor ,Humans ,Mice, Transgenic ,Neoplasms, Experimental ,Oxidation-Reduction ,Tumor Microenvironment ,Intracellular ,MESH: Cell Line, Tumor ,[SDV.IMM] Life Sciences [q-bio]/Immunology ,Regulatory T cell ,MESH: Mice, Transgenic ,T cell ,chemical and pharmacologic phenomena ,Cell Line ,03 medical and health sciences ,Experimental ,Fatty acid synthesi ,medicine ,MESH: Mice ,MESH: Humans ,Fatty acid metabolism ,MESH: T-Lymphocytes, Regulatory ,Lipid metabolism ,030104 developmental biology - Abstract
International audience; 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.
- Published
- 2018
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