Redirecting glucose flux during invitro expansion generates epigenetically and metabolically superior Tcells for cancer immunotherapy.

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Cellular therapies are living drugs whose efficacy depends on persistence and survival. Expansion of therapeutic Tcells employs hypermetabolic culture conditions to promote Tcell expansion. We show that typical invitro expansion conditions generate metabolically and functionally impaired Tcells more reliant on aerobic glycolysis than those expanding invivo. We used dichloroacetate (DCA) to modulate glycolytic metabolism during expansion, resulting in elevated mitochondrial capacity, stemness, and improved antitumor efficacy in murine Tcell receptor (TCR)-Tg and human CAR-T cells. DCA-conditioned Tcells surprisingly show no elevated intratumoral effector function but rather have improved engraftment. DCA conditioning decreases reliance on glucose, promoting usage of serum-prevalent physiologic carbon sources. Further, DCA conditioning promotes metabolic flux from mitochondria to chromatin, resulting in increased histone acetylation at key longevity genes. Thus, hyperglycemic culture conditions promote expansion at the expense of metabolic flexibility and suggest pharmacologic metabolic rewiring as a beneficial strategy for improvement of cellular immunotherapies.