MEK inhibition prevents CAR-T cell exhaustion and differentiation via downregulation of c-Fos and JunB

作者：Xiu‐Jian Wang, Tao Xiao, Pengjie Chen, Penglei Jiang, Wenxiao Li, Hefeng Chang, Cong Wei, Xinyi Lai, Hao Zhang, Yihan Pan, Lijuan Ding, Zuyu Liang, Jiazhen Cui, Mi Shao, Xinyi Teng, Tianning Gu, Jieping Wei, Delin Kong, Xiaohui Si, Yingli Han, Huarui Fu, Lin Yu, Jian Yu, Xia Li, Dongrui Wang, Yongxian Hu, Pengxu Qian, He Huang · 发表于：Signal Transduction and Targeted Therapy · 年份：2024 · DOI：10.1038/s41392-024-01986-y · 被引用次数：42 · 研究领域：CAR-T cell therapy research、Immune Cell Function and Interaction、T-cell and B-cell Immunology

Clinical evidence supports the notion that T cell exhaustion and terminal differentiation pose challenges to the persistence and effectiveness of chimeric antigen receptor-T (CAR-T) cells. MEK1/2 inhibitors (MEKIs), widely used in cancer treatment due to their ability to inhibit aberrant MAPK signaling, have shown potential synergistic effects when combined with immunotherapy. However, the impact and mechanisms of MEKIs on CAR-T cells remain uncertain and controversial. To address this, we conducted a comprehensive investigation to determine whether MEKIs enhance or impair the efficacy of CAR-T cells. Our findings revealed that MEKIs attenuated CAR-T cell exhaustion and terminal differentiation induced by tonic signaling and antigen stimulation, thereby improving CAR-T cell efficacy against hematological and solid tumors. Remarkably, these effects were independent of the specific scFvs and costimulatory domains utilized in CARs. Mechanistically, analysis of bulk and single-cell transcriptional profiles demonstrates that the effect of MEK inhibition was related to diminish anabolic metabolism and downregulation of c-Fos and JunB. Additionally, the overexpression of c-Fos or JunB in CAR-T cells counteracted the effects of MEK inhibition. Furthermore, our Cut-and-Tag assay revealed that MEK inhibition downregulated the JunB-driven gene profiles associated with exhaustion, differentiation, anergy, glycolysis, and apoptosis. In summary, our research unveil the critical role of the...