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Updated: May 13, 2025

Method for Measuring the Activity of Deubiquitinating Enzymes in Cell Lines and Tissue Samples
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Method for Measuring the Activity of Deubiquitinating Enzymes in Cell Lines and Tissue Samples

Published on: May 10, 2015

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Deubiquitinase USP24 activated by IL-6/STAT3 enhances PD-1 protein stability and suppresses T cell antitumor response

Hung-Chia Hsieh1, Ming-Jer Young2, Kuan-Yu Chen3

  • 1Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan.

Science Advances
|April 16, 2025
PubMed

Insights

Ubiquitin-specific peptidase 24 (USP24) stabilizes programmed cell death-1 (PD-1) in T cells, driving exhaustion and immunotherapy failure. Inhibiting USP24 restores T cell function and enhances cancer treatment efficacy.

Area of Science:

  • Immunology
  • Molecular Biology
  • Oncology

Background:

  • Persistent programmed cell death-1 (PD-1) signaling contributes to T cell exhaustion and immunotherapy resistance.
  • The precise mechanisms regulating PD-1 deubiquitination and subsequent T cell dysfunction are not fully understood.

Purpose of the Study:

  • To elucidate the role of ubiquitin-specific peptidase 24 (USP24) in PD-1 protein stability and T cell function.
  • To investigate USP24 as a potential therapeutic target for enhancing cancer immunotherapy.

Main Methods:

  • Investigated the deubiquitinating activity of USP24 on PD-1 using biochemical assays.
  • Utilized cell-based assays and genetically modified mouse models (including catalytic-deficient mice) to study USP24 function in T cells and lung tumorigenesis.
  • Administered USP24-specific inhibitors and combination immunotherapies (anti-CTLA4) in preclinical models.
  • Analyzed clinical samples from lung cancer patients to correlate USP24 expression with T cell exhaustion and immunotherapy response.

Main Results:

  • USP24 deubiquitinates PD-1 by removing K48-linked polyubiquitin, thereby stabilizing the PD-1 protein.
  • Interleukin-6 (IL-6) upregulates USP24 expression, leading to increased PD-1 stability.
  • USP24 deficiency in mice reduced PD-1 levels in CD8+ T cells and attenuated EGFR-driven lung tumorigenesis.
  • A USP24-specific inhibitor (USP24-i-101) enhanced cytotoxic T cell activity, suppressed tumor growth, and improved outcomes when combined with anti-CTLA4 therapy.
  • High USP24 expression in tumor-infiltrating CD8+ T cells from lung cancer patients correlated with T cell exhaustion and poor immunotherapy response.

Conclusions:

  • USP24 plays a critical role in maintaining PD-1 stability within tumor-infiltrating CD8+ T cells.
  • USP24 represents a novel therapeutic target for overcoming T cell exhaustion and improving the efficacy of cancer immunotherapy, particularly in lung cancer.

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