Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 28, Pages E6546-E6555Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1720113115
Keywords
Treg; tumor microenvironment; glycolysis; fatty acid synthesis; ox40
Categories
Funding
- Associazione Italiana per la Ricerca sul Cancro [IG-2014 15199, IG-2017 19939, IG-2017 19784]
- Ministry of Education, University and Research (MIUR) [RF-2010-2310438, RF 2010-2318269]
- Fondazione Italiana Sclerosi Multipla [2015/R/04, 2013/R/9, 2016/R/18, 2014/R/19]
- MIUR Progetti di Ricerca di Interesse Nazionale [2010LC747T_004]
- MIUR Fondo per gli Investimenti della Ricerca di Base [RBAP10TPXK]
- Istituto Pasteur Italia-Fondazione Cenci Bolognetti Grant
- International Network Institut Pasteur Programmes Transversaux de Recherche [20-16]
- Fondazione Roma Grant for Biomedical Research [NCDS-2013-000000345]
- European Union [259743]
- Fondazione Cariplo [20160852]
- Ministero della Salute [GR-2011-02346974, GR-2013-02355011]
- European Union IDEAS Programme European Research Council [310496]
- Telethon Grant [GGP17086]
- Fondazione Veronesi
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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.
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