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Hip1R Targets Pd-L1 To Lysosomal D.egradation To Alter T C ell-Mediated Cytotoxicity

文献类型： 外文期刊

作者： Wang, HB; Yao, H; Li, CS; Shi, HB; Lan, J; Li, ZL; Zhang, Y; Liang, LX; Fang, JY; Xu, J

作者机构：

期刊名称： NATURE CHEMICAL BIOLOGY

ISSN： 1552-4450

年卷期： 2019 年 15 卷 1 期

页码：

收录情况： JCR（2021版）

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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