细胞毒性
溶酶体
化学
PD-L1
细胞生物学
T细胞
免疫系统
癌症研究
生物
生物化学
免疫疗法
免疫学
体外
酶
作者
Huanbin Wang,Han Yao,Chushu Li,Hubing Shi,Lan Jiang,Zhaoli Li,Y Zhang,Lunxi Liang,Jing‐Yuan Fang,Jie Xu
标识
DOI:10.1038/s41589-018-0161-x
摘要
Expression of programmed cell death 1 (PD-1) ligand 1 (PD-L1) protects tumor cells from T cell-mediated immune surveillance, and immune checkpoint blockade (ICB) therapies targeting PD-1 and PD-L1 have exhibited significant clinical benefits. However, the relatively low response rate and observed ICB resistance highlight the need to understand the molecular regulation of PD-L1. Here we show that HIP1R targets PD-L1 to lysosomal degradation to alter T cell-mediated cytotoxicity. HIP1R physically interacts with PD-L1 and delivers PD-L1 to the lysosome through a lysosomal targeting signal. Depletion of HIP1R in tumor cells caused PD-L1 accumulation and suppressed T cell-mediated cytotoxicity. A rationally designed peptide (PD-LYSO) incorporating the lysosome-sorting signal and the PD-L1-binding sequence of HIP1R successfully depleted PD-L1 expression in tumor cells. Our results identify the molecular machineries governing the lysosomal degradation of PD-L1 and exemplify the development of a chimeric peptide for targeted degradation of PD-L1 as a crucial anticancer target.
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