2. Academic Validation
  3. Targeting a disintegrin and metalloprotease (ADAM) 17-CD122 axis enhances CD8+ T cell effector differentiation and anti-tumor immunity

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

  • Signal Transduct Target Ther. 2024 Jun 26;9(1):152. doi: 10.1038/s41392-024-01873-6.
Lina Sun # 1 2 3 4,  Anjun Jiao # 1 2 3 4,  Haiyan Liu # 1 2,  Renyi Ding 1 2,  Ning Yuan 1 2,  Biao Yang 1 2,  Cangang Zhang 1 2,  Xiaoxuan Jia 2,  Gang Wang 5,  Yanhong Su 1 2 3 4,  Dan Zhang 1 2,  Lin Shi 1 2 4,  Chenming Sun 6 7 8 9,  Aijun Zhang 10,  Lianjun Zhang 11 12,  Baojun Zhang 13 14 15 16
Affiliations

Affiliations

  • 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 Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China. cm.sun@xjtu.edu.cn.
  • 7 Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China. cm.sun@xjtu.edu.cn.
  • 8 Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, 710061, China. cm.sun@xjtu.edu.cn.
  • 9 Xi'an Key Laboratory of Immune Related Diseases, Xi'an, Shannxi, 710061, China. cm.sun@xjtu.edu.cn.
  • 10 Department of Pediatrics, Qilu Hospital of Shandong University, Jinan, China. zhangaijun@sdu.edu.cn.
  • 11 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. zlj@ism.cams.cn.
  • 12 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. zlj@ism.cams.cn.
  • 13 Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China. bj.zhang@mail.xjtu.edu.cn.
  • 14 Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China. bj.zhang@mail.xjtu.edu.cn.
  • 15 Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, 710061, China. bj.zhang@mail.xjtu.edu.cn.
  • 16 Xi'an Key Laboratory of Immune Related Diseases, Xi'an, Shannxi, 710061, China. bj.zhang@mail.xjtu.edu.cn.
  • # Contributed equally.
PMID: 38918390 DOI: 10.1038/s41392-024-01873-6
Abstract

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 cell-specific 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.

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