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
  • 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. [email protected].
  • 7. Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China. [email protected].
  • 8. Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, 710061, China. [email protected].
  • 9. Xi'an Key Laboratory of Immune Related Diseases, Xi'an, Shannxi, 710061, China. [email protected].
  • 10. Department of Pediatrics, Qilu Hospital of Shandong University, Jinan, China. [email protected].
  • 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. [email protected].
  • 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. [email protected].
  • 13. Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China. [email protected].
  • 14. Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China. [email protected].
  • 15. Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, 710061, China. [email protected].
  • 16. Xi'an Key Laboratory of Immune Related Diseases, Xi'an, Shannxi, 710061, China. [email protected].
  • # 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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