期刊
NATURE CHEMICAL BIOLOGY
卷 15, 期 1, 页码 42-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41589-018-0161-x
关键词
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资金
- National Key Research & Development (RD) Plan [2016YFC0906002]
- National Natural Science Foundation of China [81874050, 81572326, 81322036, 81320108024]
- Top-Notch Young Talents Program of China [ZTZ2015-48]
- Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support [20152514]
- Shanghai Municipal Education Commission
- Shanghai Education Development Foundation [15SG16]
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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