Cell Rep 2019 May 14; 27(7):2063-74.
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, Jing; Villa, Matteo; Sanin, David E; Buck, Michael D; O'Sullivan, David; Ching, Reagan; Matsushita, Mai; Grzes, Katarzyna M; Winkler, Frances; Chang, Chih-Hao; Curtis, Jonathan D; Kyle, Ryan L; Van Teijlingen Bakker, Nikki; Corrado, Mauro; Haessler, Fabian; Alfei, Francesca; Edwards-Hicks, Joy; Maggi, Leonard B; Zehn, Dietmar; Egawa, Takeshi; Bengsch, Bertram; Klein Geltink, Ramon I; Jenuwein, Thomas; Pearce, Edward J; and Pearce, Erika L, "Acetate Promotes T Cell Effector Function during Glucose Restriction." (2019). Faculty Research 2019. 116.