Acetate Promotes T Cell Effector Function during Glucose Restriction

摘要

Competition for nutrients like glucose can metabolicallyrestrict T cells and contribute to their hyporesponsivenessduring cancer. Metabolic adaptationto the surrounding microenvironment is thereforekey for maintaining appropriate cell function. Forinstance, cancer cells use acetate as a substratealternative to glucose to fuel metabolism and growth.Here, we show that acetate rescues effector functionin glucose-restricted CD8+ T cells. Mechanistically,acetate promotes histone acetylation and chromatinaccessibility and enhances IFN-g gene transcriptionand cytokine production in an acetyl-CoA synthetase(ACSS)-dependent manner. Ex vivo acetate treatmentincreases IFN-g production by exhaustedT cells, whereas reducing ACSS expression inT cells impairs IFN-g production by tumor-infiltratinglymphocytes and tumor clearance. Thus, hyporesponsiveT cells can be epigenetically remodeledand reactivated by acetate, suggesting that pathwaysregulating the use of substrates alternative toglucose could be therapeutically targeted to promoteT cell function during cancer.