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

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Listed:
  • Wenfeng Ren

    (Xiamen University
    Xiamen University)

  • Zilong Xu

    (Xiamen University
    Xiamen University)

  • Yating Chang

    (Xiamen University
    Xiamen University
    Xiamen University)

  • Fei Ju

    (Xiamen University
    Xiamen University)

  • Hongning Wu

    (Xiamen University
    Xiamen University
    Xiamen University)

  • Zhiqi Liang

    (Xiamen University
    Xiamen University
    Xiamen University)

  • Min Zhao

    (Xiamen University
    Xiamen University)

  • Naizhen Wang

    (Xiamen University
    Xiamen University)

  • Yanhua Lin

    (Xiamen University
    Xiamen University)

  • Chenhang Xu

    (Xiamen University
    Xiamen University
    Xiamen University)

  • Shengming Chen

    (Xiamen University
    Xiamen University)

  • Yipeng Rao

    (Xiamen University
    Xiamen University)

  • Chaolong Lin

    (Xiamen University
    Xiamen University)

  • Jianxin Yang

    (Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University
    Fujian Provincial Key Laboratory and Chronic Liver Disease and Hepatocellular Carcinoma)

  • Pingguo Liu

    (Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University
    Fujian Provincial Key Laboratory and Chronic Liver Disease and Hepatocellular Carcinoma)

  • Jun Zhang

    (Xiamen University
    Xiamen University)

  • Chenghao Huang

    (Xiamen University
    Xiamen University)

  • Ningshao Xia

    (Xiamen University
    Xiamen University
    Xiamen University)

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.

Suggested Citation

  • 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 L, 2024. "Pharmaceutical targeting of OTUB2 sensitizes tumors to cytotoxic T cells via degradation of PD-L1," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-44466-7
    DOI: 10.1038/s41467-023-44466-7
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