Mitochondrial isocitrate dehydrogenase impedes CAR T cell function by restraining antioxidant metabolism and histone acetylation

Abstract

The efficacy of chimeric antigen receptor (CAR) Tcell therapy is hampered by relapse in hematologic malignancies and by hyporesponsiveness in solid tumors. Long-lived memory CAR Tcells are critical for improving tumor clearance and long-term protection. However, during rapid exvivo expansion or invivo tumor eradication, metabolic shifts and inhibitory signals lead to terminal differentiation and exhaustion of CAR Tcells. Through a mitochondria-related compound screening, we find that the FDA-approved isocitrate dehydrogenase 2 (IDH2) inhibitor enasidenib enhances memory CAR Tcell formation and sustains anti-leukemic cytotoxicity invivo. Mechanistically, IDH2 impedes metabolic fitness of CAR Tcells by restraining glucose utilization via the pentose phosphate pathway, which alleviates oxidative stress, particularly in nutrient-restricted conditions. In addition, IDH2 limits cytosolic acetyl-CoA levels to prevent histone acetylation that promotes memory cell formation. In combination with pharmacological IDH2 inhibition, CAR Tcell therapy is demonstrated to have superior efficacy in a pre-clinical model.