Acetate Promotes T Cell Effector Function during Glucose Restriction

Jing Qiu, Matteo Villa, David E. Sanin, Michael D. Buck, David O'Sullivan, Reagan Ching, Mai Matsushita, Katarzyna M. Grzes, Frances Winkler, Chih Hao Chang, Jonathan D. Curtis, Ryan L. Kyle, Nikki Van Teijlingen Bakker, Mauro Corrado, Fabian Haessler, Francesca Alfei, Joy Edwards-Hicks, Leonard B. Maggi, Dietmar Zehn, Takeshi EgawaBertram Bengsch, Ramon I. Klein Geltink, Thomas Jenuwein, Edward J. Pearce, Erika L. Pearce

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Competition for nutrients like glucose can metabolically restrict T cells and contribute to their hyporesponsiveness during cancer. Metabolic adaptation to the surrounding microenvironment is therefore key for maintaining appropriate cell function. For instance, cancer cells use acetate as a substrate alternative to glucose to fuel metabolism and growth. Here, we show that acetate rescues effector function in glucose-restricted CD8+ T cells. Mechanistically, acetate promotes histone acetylation and chromatin accessibility and enhances IFN-γ gene transcription and cytokine production in an acetyl-CoA synthetase (ACSS)-dependent manner. Ex vivo acetate treatment increases IFN-γ production by exhausted T cells, whereas reducing ACSS expression in T cells impairs IFN-γ production by tumor-infiltrating lymphocytes and tumor clearance. Thus, hyporesponsive T cells can be epigenetically remodeled and reactivated by acetate, suggesting that pathways regulating the use of substrates alternative to glucose could be therapeutically targeted to promote T cell function during cancer. Qiu et al. show that acetate enhances histone acetylation, chromatin accessibility, and effector function in glucose-restricted CD8+ T cells. The authors find that manipulation of acetate-handling pathways influences cytokine production of tumor-infiltrating CD8+ T cells, which could have therapeutic implications for activating CD8+ T cell effector function in the tumor microenvironment.

Original languageEnglish
Pages (from-to)2063-2074.e5
JournalCell Reports
Volume27
Issue number7
DOIs
StatePublished - May 14 2019

Keywords

  • T cell exhaustion
  • T cell hyporesponsiveness
  • T cells
  • acetate
  • acetyl-CoA synthetase
  • chromatin remodeling
  • effector functions
  • tumor immunity
  • tumor-infiltrating lymphocytes

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  • Cite this

    Qiu, J., Villa, M., Sanin, D. E., Buck, M. D., O'Sullivan, D., Ching, R., Matsushita, M., Grzes, K. M., Winkler, F., Chang, C. H., Curtis, J. D., Kyle, R. L., Van Teijlingen Bakker, N., Corrado, M., Haessler, F., Alfei, F., Edwards-Hicks, J., Maggi, L. B., Zehn, D., ... Pearce, E. L. (2019). Acetate Promotes T Cell Effector Function during Glucose Restriction. Cell Reports, 27(7), 2063-2074.e5. https://doi.org/10.1016/j.celrep.2019.04.022