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Abstract Persistent programmed cell death-1 (PD-1) /PD-L1 inhibitory signaling disrupts T cell cytotoxic function, leading to T cell exhaustion—a phenomenon strongly associated with advanced cancer progression and immunotherapy failure. Deciphering the mechanisms behind dysregulated PD-1 expression and reactivating tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment (TME) is crucial. Our previous research established that tumor-associated macrophage-derived IL-6 promotes STAT3-dependent PD-1 transcriptional activity and immunotherapy resistance. The current study further explores whether IL-6 abundance in the TME contributes to PD-1 protein stability. Results indicate that IL-6 extended PD-1 protein half-life in T cells, suggesting its role in modulating PD-1 protein stability. Furthermore, analysis of the GEO database showed a positive correlation between the expression of ubiquitin-specific-processing protease (USP) family enzymes and PD-1 in non-responding patients receiving anti-PD-1 therapy. Knockdown experiments revealed that USP24 strongly downregulated PD-1 protein expression and stability. USP24 depletion reversed IL-6-induced PD-1 expression and stability, with USP24 colocalizing with PD-1 at the plasma membrane upon IL-6 stimulation. Immunoprecipitation-Western blot assays confirmed that USP24 directly interacted with PD-1 and countered E3 ligase c-Cbl-mediated ubiquitination. Depleting USP24 suppressed PD-1-mediated immunosuppression both in vitro and in vivo. In lung-specific EGFRL858R/USP24C1698A functional knockout mice, tumor progression was slower, and exhausted tumor-infiltrating PD-1+ TIM-3+ CD8+ T cells reduced compared to EGFRL858R mice. Inhibiting PD-1 stability with an IL-6 neutralizing antibody or the novel inhibitor USP24-i-101 decreased tumor volume and increased activated cytotoxic T cell infiltration in vivo. Moreover, USP24-i-101 enhanced therapeutic effects in combination with anti-CTLA4 immunotherapy. Clinically, our in-house cohort revealed elevated USP24 expression in tumor-infiltrating lymphocytes or peripheral T cells, correlating with worse clinical outcomes and unfavorable responses to immunotherapy in lung cancer patients. This study uncovers USP24 as a novel PD-1 regulator, deubiquitinating PD-1 to enhance protein stability and suppress T cell function. In conclusion, USP24 emerges as a potential target for enhancing anti-tumor immunity and as a biomarker predicting clinical responses to immunotherapy in lung cancer. Citation Format: Hung-Chia Hsieh, Jan-Jong Hung, Yi-Ching Wang. USP24 suppresses T cell anti-tumor activity by enhancing the stability of the PD-1 protein abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr LB445.
Hsieh et al. (Fri,) studied this question.