Intracellular Acetyl CoA Potentiates the Therapeutic Efficacy of Antitumor CD8(+) T Cells

Effector CD8(+) T cells rely primarily on glucose metabolism to meet their biosynthetic and functional needs. However, nutritional limitations in the tumor microenvironment can cause T-cell hypo-responsiveness. Therefore, T cells must acquire metabolic traits enabling sustained effector function at the tumor site to elicit a robust antitumor immune response. Here, we report that IL12-stimulated CD8(+) T cells have elevated intracellular acetyl CoA levels and can maintain IFN gamma levels in nutrient-deprived, tumor-conditioned media (TCM). Pharmacological and metabolic analy-ses demonstrated an active glucose-citrate-acetyl CoA circuit in IL12-stimulated CD8+ T cells supporting an intracellular pool of acetyl CoA in an ATP-citrate lyase (ACLY)-dependent manner. Intracellular acetyl CoA levels enhanced histone acetylation, lipid synthesis, and IFN gamma production, improving the metabolic and functional fitness of CD8(+) T cells in tumors. Pharmacological inhibition or genetic knockdown of ACLY severely impaired IFN gamma production and viability of CD8(+) T cells in nutrient-restricted conditions. Furthermore, CD8(+) T cells cultured in high pyru-vate-containing media in vitro acquired critical metabolic features of IL12-stimulated CD8(+) T cells and displayed improved antitumor potential upon adoptive transfer in murine lymphoma and mela-noma models. Overall, this study delineates the metabolic config-uration of CD8(+) T cells required for stable effector function in tumors and presents an affordable approach to promote the efficacy of CD8(+) T cells for adoptive T-cell therapy. Significance:IL12-mediated metabolic reprogramming increases intracellular acetyl CoA to promote the effector function of CD8 thorn T cells in nutrient-depleted tumor microenvironments, revealing strategies to potentiate the antitumor efficacy of T cells.