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

Cell Metab. 2024 Jan 2;36(1):176-192.e10. doi: 10.1016/j.cmet.2023.12.010.ABSTRACTThe efficacy of chimeric antigen receptor (CAR) T cell therapy is hampered by relapse in hematologic malignancies and by hyporesponsiveness in solid tumors. Long-lived memory CAR T cells are critical for improving tumor clearance and long-term protection. However, during rapid ex vivo expansion or in vivo tumor eradication, metabolic shifts and inhibitory signals lead to terminal differentiation and exhaustion of CAR T cells. Through a mitochondria-related compound screening, we find that the FDA-approved isocitrate dehydrogenase 2 (IDH2) inhibitor enasidenib enhances memory CAR T cell formation and sustains anti-leukemic cytotoxicity in vivo. Mechanistically, IDH2 impedes metabolic fitness of CAR T cells 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 T cell therapy is demonstrated to have superior efficacy in a pre-clinical model.PMID:38171332 | DOI:10.1016/j.cmet.2023.12.010

Source: Cell Metabolism - January 3, 2024 Category: Cytology Authors: Xiaohui Si Mi Shao Xinyi Teng Yue Huang Ye Meng Longyuan Wu Jieping Wei Lianxuan Liu Tianning Gu Junzhe Song Ruirui Jing Xingyuan Zhai Xin Guo Delin Kong Xiujian Wang Bohan Cai Ying Shen Zhaoru Zhang Dongrui Wang Yongxian Hu Pengxu Qian Gang Xiao He Huang Source Type: research