Pharmaceutical targeting of OTUB2 sensitizes tumors to cytotoxic T cells via degradation of PD-L1

Wenfeng Ren, Zilong Xu, Yating Chang, Fei Ju, Hongning Wu, Zhiqi Liang, Min Zhao, Naizhen Wang, Yanhua Lin, Chenhang Xu, Shengming Chen, Yipeng Rao, Chaolong Lin, Jianxin Yang, Pingguo Liu (), Jun Zhang (), Chenghao Huang () and Ningshao Xia ()
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Wenfeng Ren: Xiamen University
Zilong Xu: Xiamen University
Yating Chang: Xiamen University
Fei Ju: Xiamen University
Hongning Wu: Xiamen University
Zhiqi Liang: Xiamen University
Min Zhao: Xiamen University
Naizhen Wang: Xiamen University
Yanhua Lin: Xiamen University
Chenhang Xu: Xiamen University
Shengming Chen: Xiamen University
Yipeng Rao: Xiamen University
Chaolong Lin: Xiamen University
Jianxin Yang: Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University
Pingguo Liu: Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University
Jun Zhang: Xiamen University
Chenghao Huang: Xiamen University
Ningshao Xia: Xiamen University

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract PD-1 is a co-inhibitory receptor expressed by CD8+ T cells which limits their cytotoxicity. PD-L1 expression on cancer cells contributes to immune evasion by cancers, thus, understanding the mechanisms that regulate PD-L1 protein levels in cancers is important. Here we identify tumor-cell-expressed otubain-2 (OTUB2) as a negative regulator of antitumor immunity, acting through the PD-1/PD-L1 axis in various human cancers. Mechanistically, OTUB2 directly interacts with PD-L1 to disrupt the ubiquitination and degradation of PD-L1 in the endoplasmic reticulum. Genetic deletion of OTUB2 markedly decreases the expression of PD-L1 proteins on the tumor cell surface, resulting in increased tumor cell sensitivity to CD8+ T-cell-mediated cytotoxicity. To underscore relevance in human patients, we observe a significant correlation between OTUB2 expression and PD-L1 abundance in human non-small cell lung cancer. An inhibitor of OTUB2, interfering with its deubiquitinase activity without disrupting the OTUB2-PD-L1 interaction, successfully reduces PD-L1 expression in tumor cells and suppressed tumor growth. Together, these results reveal the roles of OTUB2 in PD-L1 regulation and tumor evasion and lays down the proof of principle for OTUB2 targeting as therapeutic strategy for cancer treatment.

Date: 2024
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DOI: 10.1038/s41467-023-44466-7

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