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

Ilenia Pacella 1 Claudio Procaccini 2 Chiara Focaccetti 1 Stefano Miacci 1 Eleonora Timperi 1 Deriggio Faicchia 2 Martina Severa 3 Fabiana Rizzo 3 Eliana Marina Coccia 3 Fabrizia Bonacina 4 Nico Mitro 4 Giuseppe Danilo Norata 4, 5 Grazisa Rossetti 6 Valeria Ranzani 6 Massimiliano Pagani 6, 4 Ezio Giorda 7 Yu Wei 8 Giuseppe Matarese 2, 9, * Vincenzo Barnaba 1, 10, 11, * Silvia Piconese 1, 10, *
* Corresponding author
1 Università degli Studi di Roma "La Sapienza" [Rome]
2 CNR - Consiglio Nazionale delle Ricerche [Napoli]
3 Istituto Superiore di Sanita [Rome]
4 Università degli studi di Milano [Milano]
5 Curtin University [Perth]
6 INGM - Istituto Nazionale Genetica Molecolare [Milano]
7 IRCCS - Istituto di Ricovero e Cura a Carattere Scientifico
8 PVHB - Pathogenèse des Virus de l'Hépatite B
9 Università degli studi di Napoli Federico II
10 Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti
11 IIT - Istituto Italiano di Tecnologia
Abstract : 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.
Keywords : ox40 glycolysis fatty acid synthesis Treg tumor microenvironment
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Ilenia Pacella, Claudio Procaccini, Chiara Focaccetti, Stefano Miacci, Eleonora Timperi, et al.. Fatty acid metabolism complements glycolysis in the selective regulatory T cell expansion during tumor growth. Proceedings of the National Academy of Sciences of the United States of America , National Academy of Sciences, 2018, 115 (28), pp.E6546-E6555. ⟨10.1073/pnas.1720113115⟩. ⟨pasteur-02572292⟩

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