Targeting a disintegrin and metalloprotease(ADAM)17-CD122 axis enhances CD8^(+)T cell effector differentiation and anti-tumor immunity  

作　　者：Lina Sun Anjun Jiao Haiyan Liu Renyi Ding Ning Yuan Biao Yang Cangang Zhang Xiaoxuan Jia Gang Wang Yanhong Su Dan Zhang Lin Shi Chenming Sun Aijun Zhang Lianjun Zhang Baojun Zhang 

机构地区：[1]Department of Pathogenic Microbiology and Immunology,School of Basic Medical Sciences,Xi’an Jiaotong University,Xi’an,Shaanxi 710061,China [2]Institute of Infection and Immunity,Translational Medicine Institute,Xi’an Jiaotong University Health Science Center,Xi’an,Shaanxi 710061,China [3]Key Laboratory of Environment and Genes Related to Diseases,Ministry of Education,Xi’an,Shaanxi 710061,China [4]Xi’an Key Laboratory of Immune Related Diseases,Xi’an,Shannxi 710061,China [5]Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy,Cancer Institute,Xuzhou Medical University,Xuzhou,Jiangsu,China [6]Department of Pediatrics,Qilu Hospital of Shandong University,Jinan,China [7]National Key Laboratory of Immunity and Inflammation,Suzhou Institute of Systems Medicine,Chinese Academy of Medical Sciences&Peking Union Medical College,Suzhou 215123 Jiangsu,China [8]Key Laboratory of Synthetic Biology Regulatory Elements,Suzhou Institute of Systems Medicine,Chinese Academy of Medical Sciences&Peking Union Medical College,Suzhou 215123 Jiangsu,China

出　　处：《Signal Transduction and Targeted Therapy》2024年第7期3097-3111,共15页信号转导与靶向治疗（英文）

基　　金：supported by grants from the National Key Research and Development Program of China 2021YFA1100702(to B.Z.);National Natural Science Foundation of China grants 82271792(to L.S.),32200727(to L.S.)and 82071828(to C.S.);Innovation Capability Support Program of Shaanxi Province 2024CX-GXPT-45(to C.S.);Natural Science Foundation of Shaanxi Province 2017JM8148(to Lin Shi);Fundamental Research Funds for the Central Universities xtr072022002(to B.Z.);the National Natural Science Foundation of China 82350114(to L.Z.);the Natural Science Foundation Outstanding Youth Fund of Jiangsu Province BK20220049(to L.Z.);Suzhou Municipal Key Laboratory SZS2023005(to L.Z.).

摘　　要：CD8^(+)T cell immune responses are regulated by multi-layer networks,while the post-translational regulation remains largely unknown.Transmembrane ectodomain shedding is an important post-translational process orchestrating receptor expression and signal transduction through proteolytic cleavage of membrane proteins.Here,by targeting the sheddase A Disintegrin and Metalloprotease(ADAM)17,we defined a post-translational regulatory mechanism mediated by the ectodomain shedding in CD8^(+)T cells.Transcriptomic and proteomic analysis revealed the involvement of post-translational regulation in CD8^(+)T cells.T cellspecific deletion of ADAM17 led to a dramatic increase in effector CD8^(+)T cell differentiation and enhanced cytolytic effects to eliminate pathogens and tumors.Mechanistically,ADAM17 regulated CD8^(+)T cells through cleavage of membrane CD122.ADAM17 inhibition led to elevated CD122 expression and enhanced response to IL-2 and IL-15 stimulation in both mouse and human CD8^(+)T cells.Intriguingly,inhibition of ADAM17 in CD8^(+)T cells improved the efficacy of chimeric antigen receptor(CAR)T cells in solid tumors.Our findings reveal a critical post-translational regulation in CD8^(+)T cells,providing a potential therapeutic strategy of targeting ADAM17 for effective anti-tumor immunity.

关 键 词：immunity stimulation INVOLVEMENT 

分 类 号：R730.3[医药卫生—肿瘤]