ITPRIPL1 binds CD3 8 to impede T cell activation and enable tumor immune evasion

被引：22

作者：

Deng, Shouyan ^{[1
]}

Zhang, Yibo ^{[1
]}

Wang, Huanbin ^{[2
]}

Liang, Wenhua ^{[3
]}

Xie, Lu ^{[4
]}

Li, Ning ^{[5
]}

Fang, Yuan ^{[5
]}

Wang, Yiting ^{[1
]}

Liu, Jiayang ^{[1
]}

Chi, Hao ^{[1
]}

Sun, Yufan ^{[2
]}

Ye, Rui ^{[2
]}

Shan, Lishen ^{[2
]}

Shi, Jiawei ^{[1
]}

Shen, Zan ^{[6
]}

Wang, Yonggang ^{[5
]}

Wang, Shuhang ^{[5
]}

Brosseau, Jean-Philippe ^{[7
]}

Wang, Feng ^{[3
]}

Liu, Grace ^{[8
]}

Quan, Yingfei ^{[2
]}

Xu, Jie ^{[1
]}

机构：

[1] Fudan Univ, Zhongshan Xuhui Hosp, Inst Biomed Sci, Shanghai Key Lab Med Epigenet,Int Colab Med Epigen, Zhongshan 200032, Shanghai, Peoples R China

[2] BioTroy Therapeut, Shanghai 201400, Peoples R China

[3] Shanghai Jiao Tong Univ, Shanghai Inst Immunol, Sch Med, Shanghai 200031, Peoples R China

[4] Peking Univ, Peoples Hosp, Musculoskeletal Tumor Ctr, Beijing 100044, Peoples R China

[5] Chinese Acad Med Sci & Peking Union Med Coll, Clin Trials Ctr, Natl Canc Ctr, Natl Clin Res Ctr Canc,Canc Hosp, Beijing 100020, Peoples R China

[6] Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 6, Sch Med, 600 Yishan Rd, Shanghai 200233, Peoples R China

[7] Univ Sherbrooke, Fac Med & Hlth Sci, Dept Biochem & Funct Genom, Sherbrooke, PQ J1E 4K8, Canada

[8] Arctic Anim Hosp, Fuzhou 350007, Fujian, Peoples R China

来源：

CELL | 2024年 / 187卷 / 09期

基金：

中国国家自然科学基金;

关键词：

GENE; EXPRESSION; ANTIBODIES; THERAPY; SITE; IMMUNOTHERAPY; TOLERANCE; TRIGGERS; BLOCKADE; FEATURES;

D O I：

10.1016/j.cell.2024.03.019

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 CD3 epsilon, and its expression inhibits T cells in the tumor microenvironment. The binding of ITPRIPL1 extracellular domain to CD3 epsilon 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, CD3 epsilon 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.

引用

页码：2305 / 2323.e33

页数：53

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