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USP2 promotes tumor immune evasion via deubiquitination and stabilization of PD-L1
Zean Kuang1, Xiaojia Liu2, Na Zhang1
1Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.
Abstract:
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.
Insights
Ubiquitin-specific processing protease 2 (USP2) stabilizes programmed death ligand-1 (PD-L1) in cancer cells. Inhibiting USP2 reduces PD-L1, enhancing anti-tumor immunity and T-cell mediated killing, suggesting USP2 as a therapeutic target.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Programmed death ligand-1 (PD-L1) upregulation on tumor cells inhibits T-cell cytotoxicity via PD-1 engagement.
- Understanding PD-L1 regulation mechanisms is crucial for improving PD-L1 blockade therapy efficacy.
Purpose of the Study:
- To identify novel regulators of PD-L1 stabilization in cancer.
- To investigate the role of ubiquitin-specific processing protease 2 (USP2) in PD-L1 regulation and its impact on anti-tumor immunity.
Main Methods:
- Utilized a single-guide RNA (sgRNA) screening system to identify PD-L1 regulators.
- Performed protein interaction assays and ubiquitination analysis to study USP2-PD-L1 interaction.
- Assessed the effects of USP2 depletion on PD-L1 levels, cancer cell sensitivity to T-cell killing, and anti-tumor immunity in mouse models.
- Analyzed clinical tissue samples for USP2 and PD-L1 expression correlation.
Main Results:
- Identified USP2 as a novel regulator that directly interacts with and stabilizes PD-L1 in colorectal and prostate cancer cells.
- USP2 deconjugates K48-linked polyubiquitination at lysine 270 of PD-L1, preventing its degradation.
- USP2 depletion leads to ER-associated degradation of PD-L1, enhancing T-cell mediated killing and anti-tumor immunity in mice.
- USP2 expression is positively associated with PD-L1 levels in clinical cancer samples.
- Combination of USP2 depletion with anti-PD-1 therapy showed synergistic anti-tumor effects.
Conclusions:
- USP2 plays a critical role in stabilizing PD-L1 in tumor cells, promoting immune evasion.
- Targeting USP2 represents a promising strategy to enhance cancer immunotherapy by reducing PD-L1 and boosting anti-tumor immunity.
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