浙江大学医学院He Huang，Gang Xiao和Pengxu Qian共同合作，近期取得重要工作进展。他们研究发现，线粒体异柠檬酸脱氢酶通过抑制抗氧化代谢和组蛋白乙酰化来阻碍CAR T细胞功能。相关研究成果2024年1月2日在线发表于《细胞—代谢》杂志上。

据介绍，嵌合抗原受体（CAR）T细胞治疗的疗效受到血液系统恶性肿瘤复发和实体瘤低反应性的阻碍。长期记忆CAR T细胞对于提高肿瘤清除率和长期保护至关重要。然而，在快速体外扩增或体内肿瘤根除过程中，代谢变化和抑制信号导致CAR T细胞的终末分化和耗竭。

通过线粒体相关化合物筛选，研究人员发现美国食品药品监督管理局（FDA）批准的异柠檬酸脱氢酶2（IDH2）抑制剂enasidenib可在体内增强记忆CAR T细胞的形成并维持抗白血病细胞毒性。从机制上讲，IDH2通过磷酸戊糖途径抑制葡萄糖的利用，从而阻碍CAR T细胞的代谢适应性，缓解氧化应激，特别是在营养受限的条件下。

此外，IDH2限制胞质乙酰辅酶A水平，以防止促进记忆细胞形成的组蛋白乙酰化。

总之，结合药理学IDH2抑制，研究人员表明，CAR T细胞治疗在临床前模型中被证明具有优越的疗效。

附：英文原文

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

Author: 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

Issue&Volume: 2024/01/02

Abstract: The efficacy of chimeric antigen receptor (CAR) T cell therapy is hampered by relapsein hematologic malignancies and by hyporesponsiveness in solid tumors. Long-livedmemory 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 differentiationand exhaustion of CAR T cells. Through a mitochondria-related compound screening,we find that the FDA-approved isocitrate dehydrogenase 2 (IDH2) inhibitor enasidenibenhances memory CAR T cell formation and sustains anti-leukemic cytotoxicity in vivo. Mechanistically, IDH2 impedes metabolic fitness of CAR T cells by restraining glucoseutilization via the pentose phosphate pathway, which alleviates oxidative stress,particularly in nutrient-restricted conditions. In addition, IDH2 limits cytosolicacetyl-CoA levels to prevent histone acetylation that promotes memory cell formation.In combination with pharmacological IDH2 inhibition, CAR T cell therapy is demonstratedto have superior efficacy in a pre-clinical model.

DOI: 10.1016/j.cmet.2023.12.010

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(23)00461-8