Acetate Promotes T Cell Effector Function during Glucose Restriction
2019
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, Jr. | Dietmar Zehn | Takeshi Egawa | Bertram Bengsch | Ramon I. Klein Geltink | Thomas Jenuwein | Edward J. Pearce | Erika L. Pearce
Summary: 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. Keywords: tumor-infiltrating lymphocytes, chromatin remodeling, T cells, acetate, acetyl-CoA synthetase, T cell exhaustion, T cell hyporesponsiveness, tumor immunity, effector functions
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