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USP22 Deubiquitinates CD274 to Suppress Anticancer Immunity

Xing Huang1,2, Qi Zhang3,4,5, Yu Lou3,4,5

  • 1Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. dr.huangxing@foxmail.com liangtingbo@zju.edu.cn shirleybai@zju.edu.cn.

Cancer Immunology Research
|August 11, 2019
PubMed

Insights

Ubiquitin-specific protease 22 (USP22) deubiquitinates programmed death-ligand 1 (CD274), enhancing cancer immune evasion. Targeting USP22 boosts anti-tumor immunity and improves immunotherapy efficacy in liver cancer.

Area of Science:

  • Immunology
  • Oncology
  • Biochemistry

Background:

  • Programmed cell death protein 1 (PD-1, CD279)-programmed death-ligand 1 (PD-L1, CD274) signaling is crucial for cancer immune evasion and a key target in immunotherapy.
  • Posttranslational modifications of CD274, including ubiquitination, influence immune suppression, but deubiquitination mechanisms remain unclear.

Purpose of the Study:

  • To identify novel deubiquitinases regulating CD274.
  • To investigate the role of USP22 in CD274 regulation and its impact on liver cancer progression and immunotherapy.

Main Methods:

  • Identified USP22 as a CD274 deubiquitinase through interaction studies.
  • Analyzed USP22 expression and alterations in various cancer types, particularly liver cancer.
  • Evaluated the effects of USP22 depletion on liver cancer growth, tumor immunity, and therapeutic responses in preclinical models.

Main Results:

  • USP22 directly interacts with CD274, promoting its deubiquitination and stabilization.
  • High USP22 expression in liver cancer correlates with poor patient prognosis.
  • Genetic depletion of USP22 suppressed liver cancer growth, enhanced anti-tumor immunity, and improved responses to CD274-targeted therapy and chemotherapy.

Conclusions:

  • USP22 is a novel deubiquitinase of CD274, playing a significant role in liver cancer immune evasion.
  • Targeting USP22 represents a promising strategy to enhance anti-cancer immunity and potentiate immunotherapy in CD274-amplified cancers.

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