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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We thank J. Zheng in Shanghai Jiao Tong University and X. Su in Peking University for their inspiring discussions and critical reading of the manuscript. This project was supported by the following grants to J.X.: National Key Research & Development (R&D) 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); “Shu Guang” project supported by Shanghai Municipal Education Commission and Shanghai Education Development Foundation (15SG16); Tang Scholar (SJTU-JX).
The authors declare no competing interests.
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Wang, H., Yao, H., Li, C. et al. HIP1R targets PD-L1 to lysosomal degradation to alter T cell–mediated cytotoxicity. Nat Chem Biol 15, 42–50 (2019). https://doi.org/10.1038/s41589-018-0161-x
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