2. Academic Validation
  3. Pharmaceutical targeting of OTUB2 sensitizes tumors to cytotoxic T cells via degradation of PD-L1

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

  • Nat Commun. 2024 Jan 2;15(1):9. doi: 10.1038/s41467-023-44466-7.
Wenfeng Ren # 1 2,  Zilong Xu # 1 2,  Yating Chang # 1 2 3,  Fei Ju # 1 2,  Hongning Wu # 1 2 3,  Zhiqi Liang # 1 2 3,  Min Zhao 1 2,  Naizhen Wang 1 2,  Yanhua Lin 1 2,  Chenhang Xu 1 2 3,  Shengming Chen 1 2,  Yipeng Rao 1 2,  Chaolong Lin 1 2,  Jianxin Yang 4 5,  Pingguo Liu 6 7,  Jun Zhang 8 9,  Chenghao Huang 10 11,  Ningshao Xia 12 13 14
Affiliations

Affiliations

  • 1 State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, Fujian, 361102, China.
  • 2 State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiamen University, Xiamen, Fujian, 361102, China.
  • 3 School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China.
  • 4 Department of Hepatobiliary & Pancreatic Surgery, The National Key Clinical Specialty, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361004, China.
  • 5 Fujian Provincial Key Laboratory and Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen, Fujian, 361004, China.
  • 6 Department of Hepatobiliary & Pancreatic Surgery, The National Key Clinical Specialty, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361004, China. pgliu@xmu.edu.cn.
  • 7 Fujian Provincial Key Laboratory and Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen, Fujian, 361004, China. pgliu@xmu.edu.cn.
  • 8 State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, Fujian, 361102, China. zhangj@xmu.edu.cn.
  • 9 State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiamen University, Xiamen, Fujian, 361102, China. zhangj@xmu.edu.cn.
  • 10 State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, Fujian, 361102, China. huangchenghao@xmu.edu.cn.
  • 11 State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiamen University, Xiamen, Fujian, 361102, China. huangchenghao@xmu.edu.cn.
  • 12 State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, Fujian, 361102, China. nsxia@xmu.edu.cn.
  • 13 State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiamen University, Xiamen, Fujian, 361102, China. nsxia@xmu.edu.cn.
  • 14 School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China. nsxia@xmu.edu.cn.
  • # Contributed equally.
PMID: 38167274 DOI: 10.1038/s41467-023-44466-7
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.

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