ITPRIPL1 binds CD3ε to impede T cell activation and enable tumor immune evasion

  • Cell. 2024 Apr 25;187(9):2305-2323.e33. doi: 10.1016/j.cell.2024.03.019.
Shouyan Deng  1 ,  Yibo Zhang  1 ,  Huanbin Wang  2 ,  Wenhua Liang  3 ,  Lu Xie  4 ,  Ning Li  5 ,  Yuan Fang  5 ,  Yiting Wang  1 ,  Jiayang Liu  1 ,  Hao Chi  1 ,  Yufan Sun  2 ,  Rui Ye  2 ,  Lishen Shan  2 ,  Jiawei Shi  1 ,  Zan Shen  6 ,  Yonggang Wang  6 ,  Shuhang Wang  5 ,  Jean-Philippe Brosseau  7 ,  Feng Wang  3 ,  Grace Liu  8 ,  Yingfei Quan  2 ,  Jie Xu  9
Affiliations
  • 1. Institutes of Biomedical Sciences, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Zhongshan-Xuhui Hospital, Fudan University, Shanghai 200032, China.
  • 2. BioTroy Therapeutics, Shanghai 201400, China.
  • 3. Shanghai Institute of Immunology, School of Medicine, Shanghai Jiao Tong University, Shanghai 200031, China.
  • 4. Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing 100044, China.
  • 5. Clinical Trials Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100020, China.
  • 6. Department of Oncology, Shanghai Sixth People's Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, No. 600, Yishan Road, Shanghai 200233, China.
  • 7. Department of Biochemistry and Functional Genomics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1E 4K8, Canada.
  • 8. Arctic Animal Hospital, Fuzhou, Fujian 350007, China.
  • 9. Institutes of Biomedical Sciences, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Zhongshan-Xuhui Hospital, Fudan University, Shanghai 200032, China. Electronic address: [email protected].
PMID: 38614099 DOI: 10.1016/j.cell.2024.03.019
Abstract

Cancer Immunotherapy has transformed treatment possibilities, but its effectiveness differs significantly among patients, indicating the presence of alternative pathways for immune evasion. Here, we show that ITPRIPL1 functions as an inhibitory ligand of CD3ε, and its expression inhibits T cells in the tumor microenvironment. The binding of ITPRIPL1 extracellular domain to CD3ε on T cells significantly decreased calcium influx and ZAP70 phosphorylation, impeding initial T cell activation. Treatment with a neutralizing antibody against ITPRIPL1 restrained tumor growth and promoted T cell infiltration in mouse models across various solid tumor types. The antibody targeting canine ITPRIPL1 exhibited notable therapeutic efficacy against naturally occurring tumors in pet clinics. These findings highlight the role of ITPRIPL1 (or CD3L1, CD3ε ligand 1) in impeding T cell activation during the critical "signal one" phase. This discovery positions ITPRIPL1 as a promising therapeutic target against multiple tumor types.

Keywords
CD3ε; ITPRIPL1; cancer immunotherapy; immune checkpoint; immune evasion.