复旦大学Jie Xu近期取得重要工作进展，他们研究提出，ITPRIPL1结合CD3ε能阻止T细胞活化并使肿瘤免疫逃逸。相关研究成果2024年4月12日在线发表于《细胞》杂志上。

据介绍，癌症免疫疗法改变了治疗的可能性，但其有效性因患者而异，这表明存在免疫逃避的替代途径。

研究人员发现ITPRIPL1作为CD3ε的抑制性配体发挥作用，其表达抑制肿瘤微环境中的T细胞。ITPRIPL1胞外结构域与T细胞上CD3ε的结合显著降低了钙流入和ZAP70磷酸化，阻碍了T细胞的初始活化。用抗ITPRIPL1的中和抗体治疗抑制了小鼠模型中各种实体瘤类型的肿瘤生长并促进T细胞浸润。靶向犬ITPRIPL1的抗体在宠物诊所对自然发生的肿瘤表现出显著的治疗效果。

总之，这些发现强调了ITPRIPL1（或CD3L1，CD3ε配体1）在关键的“信号一”阶段阻碍T细胞活化的作用。这一发现将ITPRIPL1定位为对抗多种肿瘤类型的有前景的治疗靶点。

附：英文原文

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

Author: Shouyan Deng, Yibo Zhang, Huanbin Wang, Wenhua Liang, Lu Xie, Ning Li, Yuan Fang, Yiting Wang, Jiayang Liu, Hao Chi, Yufan Sun, Rui Ye, Lishen Shan, Jiawei Shi, Zan Shen, Yonggang Wang, Shuhang Wang, Jean-Philippe Brosseau, Feng Wang, Grace Liu, Yingfei Quan, Jie Xu

Issue&Volume: 2024-04-12

Abstract: Cancer immunotherapy has transformed treatment possibilities, but its effectivenessdiffers significantly among patients, indicating the presence of alternative pathwaysfor immune evasion. Here, we show that ITPRIPL1 functions as an inhibitory ligandof CD3ε, and its expression inhibits T cells in the tumor microenvironment. The bindingof ITPRIPL1 extracellular domain to CD3ε on T cells significantly decreased calciuminflux and ZAP70 phosphorylation, impeding initial T cell activation. Treatment witha neutralizing antibody against ITPRIPL1 restrained tumor growth and promoted T cellinfiltration in mouse models across various solid tumor types. The antibody targetingcanine ITPRIPL1 exhibited notable therapeutic efficacy against naturally occurringtumors in pet clinics. These findings highlight the role of ITPRIPL1 (or CD3L1, CD3εligand 1) in impeding T cell activation during the critical “signal one” phase. Thisdiscovery positions ITPRIPL1 as a promising therapeutic target against multiple tumortypes.

DOI: 10.1016/j.cell.2024.03.019

Source: https://www.cell.com/cell/abstract/S0092-8674(24)00310-6