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

作　　者：Xiujian Wang Xiao Tao 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 Yu Lin Jian Yu Xia Li Dongrui Wang Yongxian Hu Pengxu Qian He Huang 

机构地区：[1]Bone Marrow Transplantation Center,The First Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou 310003,China [2]Liangzhu Laboratory,Zhejiang University Medical Center,1369 West Wenyi Road,Hangzhou 311121,China [3]Institute of Hematology,Zhejiang University,Hangzhou 310003,China [4]Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy,Hangzhou 310003,China [5]Center of Stem Cell and Regenerative Medicine,Zhejiang University School of Medicine,Hangzhou 310058,China [6]Department of Hematology,The Third Affiliated Hospital of Wenzhou Medical University,Wenzhou 325200,China

出　　处：《Signal Transduction and Targeted Therapy》2024年第11期5267-5285,共19页信号转导与靶向治疗（英文）

基　　金：supported by the National Key Research and Development Program of China(2022YFA1103500 to P.Q.);the National Key Nature Science Foundation of China(82130003 to H.H.);the Key Project of Science and Technology Department of Zhejiang Province(2019C03016 and 2020C03G2013586 to H.H.,Z24H080001 to P.Q.);the National Natural Science Foundation of China(82200248 and 82000194 to H.H.,82222003 and 82161138028 to P.Q.);the Key R&D Program of Zhejiang(2024SSYS0023 to H.H.,2024SSYS0024 to P.Q.,2024SSYS0025 to Y.H.);the Fundamental Research Funds for the Central Universities(226-2024-00007 to P.Q.).

摘　　要：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 MAPK-c-Fos-JunB axis in driving CAR-T cell exhaustion and terminal differentiation.These mechanistic insights significantly broaden the potential application of MEKIs to enhance the effectiveness of CAR-T therapy.

关 键 词：JUNB metabolism STIMULATION 

分 类 号：R392[医药卫生—免疫学]