TY - JOUR
AU1 - Kuang, Zean
AU2 - Liu, Xiaojia
AU3 - Zhang, Na
AU4 - Dong, Jingwen
AU5 - Sun, Cuicui
AU6 - Yin, Mingxiao
AU7 - Wang, Yuting
AU8 - Liu, Lu
AU9 - Xiao, Dian
AU1 - Zhou, Xinbo
AU1 - Feng, Yanchun
AU1 - Song, Danqing
AU1 - Deng, Hongbin
AB - The abnormal upregulation of programmed death ligand-1 (PD-L1) on tumor cells impedes T-cell mediated cytotoxicity through PD-1 engagement, and further exploring the mechanisms regulation of PD-L1 in cancers may enhance the clinical efficacy of PD-L1 blockade. Here, using single-guide RNAs (sgRNAs) screening system, we identify ubiquitin-specific processing protease 2 (USP2) as a novel regulator of PD-L1 stabilization for tumor immune evasion. USP2 directly interacts with and increases PD-L1 abundance in colorectal and prostate cancer cells. Our results show that Thr288, Arg292 and Asp293 at USP2 control its binding to PD-L1 through deconjugating the K48-linked polyubiquitination at lysine 270 of PD-L1. Depletion of USP2 causes endoplasmic reticulum (ER)-associated degradation of PD-L1, thus attenuates PD-L1/PD-1 interaction and sensitizes cancer cells to T cell-mediated killing. Meanwhile, USP2 ablation-induced PD-L1 clearance enhances antitumor immunity in mice via increasing CD8+ T cells infiltration and reducing immunosuppressive infiltration of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), whereas PD-L1 overexpression reverses the tumor growth suppression by USP2 silencing. USP2-depletion combination with anti-PD-1 also exhibits a synergistic anti-tumor effect. Furthermore, analysis of clinical tissue samples indicates that USP2 is positively associated with PD-L1 expression in cancer. Collectively, our data reveal a crucial role of USP2 for controlling PD-L1 stabilization in tumor cells, and highlight USP2 as a potential therapeutic target for cancer immunotherapy.[graphic not available: see fulltext]
TI - USP2 promotes tumor immune evasion via deubiquitination and stabilization of PD-L1
JF - Cell Death and Differentiation
DO - 10.1038/s41418-023-01219-9
DA - 2023-10-01
UR - https://www.deepdyve.com/lp/springer-journals/usp2-promotes-tumor-immune-evasion-via-deubiquitination-and-2V0Rk6d0v6
SP - 2249
EP - 2264
VL - 30
IS - 10
DP - DeepDyve
ER -