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ERK and USP5 govern PD-1 homeostasis via deubiquitination to modulate tumor immunotherapy

ABSTRACT: The programmed cell death protein 1 (PD-1) is an inhibitory receptor on T cells and plays an important role in promoting cancer immune evasion. While ubiquitin E3 ligases for regulating PD-1 stability have been reported, deubiquitinase (DUB) governing PD-1 homeostasis to modulate tumor immunotherapy remains unknown. Here, we identify the ubiquitin-specific protease 5 (USP5) as a bona fide deubiquitinase for PD-1. Mechanistically, USP5 interacts with PD-1, leading to deubiquitination and stabilization of PD-1. Moreover, extracellular signal-regulated kinase (ERK) phosphorylates PD-1 at Thr234 and stabilizes PD-1 through promoting PD-1/USP5 interaction. Conditional knockout (cKO) of Usp5 in T cells significantly suppresses tumor growth in mice largely through decreasing PD-1 and increasing tumor-infiltrating cytotoxic CD8+ T cells. Furthermore, co-targeting USP5 and ERK signaling has an additive effect on reducing PD-1 and suppressing tumor growth in vivo. Together, this study uncovers the molecular mechanism for ERK/USP5 axis in regulating PD-1 stability and identifies potential combined therapeutic strategies for enhancing anti-tumor efficacy.

ORGANISM(S): Homo Sapiens

SUBMITTER: Jingfang Zhang

PROVIDER: PXD040671 | iProX | Fri Mar 17 00:00:00 GMT 2023

REPOSITORIES: iProX

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ERK and USP5 govern PD-1 homeostasis via deubiquitination to modulate tumor immunotherapy.

Xiao Xiangling X Shi Jie J He Chuan C Bu Xia X Sun Yishuang Y Gao Minling M Xiang Bolin B Xiong Wenjun W Dai Panpan P Mao Qi Q Xing Xixin X Yao Yingmeng Y Yu Haisheng H Xu Gaoshan G Li Siqi S Ren Yan Y Chen Baoxiang B Jiang Congqing C Meng Geng G Lee Yu-Ru YR Wei Wenyi W Freeman Gordon J GJ Xie Conghua C Zhang Jinfang J

Nature communications 20230519 1

The programmed cell death protein 1 (PD-1) is an inhibitory receptor on T cells and plays an important role in promoting cancer immune evasion. While ubiquitin E3 ligases regulating PD-1 stability have been reported, deubiquitinases governing PD-1 homeostasis to modulate tumor immunotherapy remain unknown. Here, we identify the ubiquitin-specific protease 5 (USP5) as a bona fide deubiquitinase for PD-1. Mechanistically, USP5 interacts with PD-1, leading to deubiquitination and stabilization of P ...[more]

PMID: 37208329

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Project description:Background: Previous studies have shown that EZH2 regulates tumor PD-L1 expression at the transcriptional level and has an impact on tumor immune environment and prognosis. However, whether EZH2 can regulate PD-L1 expression at the post-translational level remains unclear. Therefore, this study aims to investigate the effects of EZH2 inhibition on PD-L1 expression and protein stability in colorectal cancer cells, uncover its underlying mechanisms, and provide new therapeutic strategies for anti-tumor immune therapy. Methods: Multiple colorectal cancer cell models were used to examine the effects of EZH2 inhibition on PD-L1 expression and protein stability at both the protein and transcriptional levels. Transcriptome analysis was performed to identify differentially expressed genes associated with EZH2 inhibition and potential effectors involved in EZH2-mediated regulation of PD-L1 protein stability. Validation of candidate genes was conducted through public database analysis and knockdown or overexpression models. Finally, the combined effects of EZH2 inhibitors and anti-PD-1 immune therapy were evaluated using a mouse xenograft model. Results: We observed that inhibition of EZH2 function upregulated PD-L1 expression and enhanced its protein stability in colorectal cancer cells. Transcriptome analysis revealed that ubiquitin-specific protease 22 (USP22) played a crucial role in mediating EZH2-regulated PD-L1 protein stability. EZH2 affected USP22 expression through its classical epigenetic regulatory function, thereby modulating PD-L1 expression stability and influencing the tumor immune microenvironment. Combination treatment with EZH2 inhibitors and anti-PD-1 immune therapy improved the tumor microenvironment, promoted immune cell infiltration, and exerted synergistic anti-cancer effects. Conclusion: This study elucidated the mechanisms by EZH2 regulate PD-L1 expression and stability, providing new insights into therapeutic strategies for colorectal cancer. The combination of EZH2 inhibitors and anti-PD-1 immune therapy can synergistically enhance anti-tumor effects. These findings offer a potential therapeutic approach to improve the effectiveness of EZH2 inhibitors in cancer treatment and contribute to a better understanding of the role of EZH2 in tumor immune regulation.

Dataset Information

ERK and USP5 govern PD-1 homeostasis via deubiquitination to modulate tumor immunotherapy

Publications

ERK and USP5 govern PD-1 homeostasis via deubiquitination to modulate tumor immunotherapy.

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