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

Ilenia Pacella, Claudio Procaccini, Chiara Focaccetti, Stefano Miacci, Eleonora Timperi, Deriggio Faicchia, Martina Severa, Fabiana Rizzo, Eliana Marina Coccia, Fabrizia Bonacina, Nico Mitro, Giuseppe Danilo Norata, Grazisa Rossetti, Valeria Ranzani, Massimiliano Pagani, Ezio Giorda, Yu Wei, Giuseppe Matarese, Vincenzo Barnaba, Silvia Piconese

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)E6546-E6555
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number28
DOIs
Publication statusPublished - Jul 10 2018

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Glycolysis
Regulatory T-Lymphocytes
Fatty Acids
Tumor Microenvironment
Growth
Neoplasms
Lipids
Lipid Metabolism
T-Lymphocytes
Glucose
Genes

Keywords

  • Animals
  • Cell Line, Tumor
  • Fatty Acid Synthase, Type I/genetics
  • Fatty Acids/genetics
  • Glycolysis/immunology
  • Humans
  • Mice
  • Mice, Transgenic
  • Neoplasm Proteins/genetics
  • Neoplasms, Experimental/genetics
  • Oxidation-Reduction
  • T-Lymphocytes, Regulatory/immunology
  • Tumor Microenvironment/genetics

Cite this

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

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 28, 10.07.2018, p. E6546-E6555.

Research output: Contribution to journalArticle

Pacella, I, Procaccini, C, Focaccetti, C, Miacci, S, Timperi, E, Faicchia, D, Severa, M, Rizzo, F, Coccia, EM, Bonacina, F, Mitro, N, Norata, GD, Rossetti, G, Ranzani, V, Pagani, M, Giorda, E, Wei, Y, Matarese, G, Barnaba, V & Piconese, S 2018, '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, vol. 115, no. 28, pp. E6546-E6555. https://doi.org/10.1073/pnas.1720113115
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. / Fatty acid metabolism complements glycolysis in the selective regulatory T cell expansion during tumor growth. In: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; Vol. 115, No. 28. pp. E6546-E6555.
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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.",
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AU - Pacella, Ilenia

AU - Procaccini, Claudio

AU - Focaccetti, Chiara

AU - Miacci, Stefano

AU - Timperi, Eleonora

AU - Faicchia, Deriggio

AU - Severa, Martina

AU - Rizzo, Fabiana

AU - Coccia, Eliana Marina

AU - Bonacina, Fabrizia

AU - Mitro, Nico

AU - Norata, Giuseppe Danilo

AU - Rossetti, Grazisa

AU - Ranzani, Valeria

AU - Pagani, Massimiliano

AU - Giorda, Ezio

AU - Wei, Yu

AU - Matarese, Giuseppe

AU - Barnaba, Vincenzo

AU - Piconese, Silvia

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N2 - 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.

AB - 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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KW - Glycolysis/immunology

KW - Humans

KW - Mice

KW - Mice, Transgenic

KW - Neoplasm Proteins/genetics

KW - Neoplasms, Experimental/genetics

KW - Oxidation-Reduction

KW - T-Lymphocytes, Regulatory/immunology

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