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

Xiangling Xiao1,2, Jie Shi1,2, Chuan He1,2

  • 1Department of Radiation and Medical Oncology, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University; Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Wuhan University, Wuhan, 430071, China.

Nature Communications
|May 19, 2023
PubMed

Insights

The ubiquitin-specific protease 5 (USP5) deubiquitinates and stabilizes programmed cell death protein 1 (PD-1). USP5 inhibition enhances anti-tumor immunity and shows potential for cancer immunotherapy combinations.

Area of Science:

  • Immunology
  • Molecular Biology
  • Oncology

Background:

  • Programmed cell death protein 1 (PD-1) is crucial for cancer immune evasion.
  • Ubiquitin E3 ligases regulating PD-1 stability are known, but deubiquitinases controlling PD-1 homeostasis remain unidentified.

Purpose of the Study:

  • To identify deubiquitinases that regulate PD-1 homeostasis.
  • To elucidate the molecular mechanism of PD-1 regulation by deubiquitinases.
  • To explore potential therapeutic strategies for enhancing anti-tumor immunity.

Main Methods:

  • Protein interaction assays to identify USP5 as a PD-1 deubiquitinase.
  • Phosphorylation site analysis of PD-1.
  • Conditional knockout of Usp5 in T cells in mouse models.
  • Combination therapy studies using USP5 inhibitors with Trametinib or anti-CTLA-4.

Main Results:

  • Ubiquitin-specific protease 5 (USP5) was identified as a deubiquitinase for PD-1.
  • USP5 deubiquitinates and stabilizes PD-1; ERK-mediated phosphorylation promotes this interaction.
  • Usp5 knockout in T cells enhanced effector cytokine production and reduced tumor growth.
  • USP5 inhibition combined with Trametinib or anti-CTLA-4 showed additive anti-tumor effects.

Conclusions:

  • A novel mechanism of ERK/USP5-mediated PD-1 regulation was described.
  • USP5 is a potential therapeutic target for enhancing cancer immunotherapy.
  • Combinatorial strategies involving USP5 inhibition show promise for improving anti-tumor efficacy.

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