研究背景: 持續性的程式性細胞死亡受體-1（PD-1）/PD-L1抑制型訊號會削弱T細胞的細胞毒性功能，最終導致T細胞耗竭，而這與晚期癌症進展及免疫療法失敗高度相關；然而，PD-1 去泛素化及 T 細胞功能失活的調控機制仍不清楚。線上資料庫分析顯示，泛素特異性胜酶 24（USP24）與T細胞功能失活及免疫療法效果不佳高度相關，但在腫瘤微環境中，USP24上調是否與PD-1蛋白穩定性有關仍有待探討。
研究目的: 本研究旨在探討USP24是否作為PD-1的去泛素化酶，從而增強PD-1穩定性，導致T細胞功能失活並降低免疫治療效果。此外，我們進一步探討調控USP24 在T細胞中表達的上游機制及其治療癌症的潛力。
研究結果: 本研究發現，USP24過度表達顯著增加PD-1蛋白表現量並增加其蛋白穩定性。免疫沉澱法證實USP24直接與PD-1結合，並拮抗E3 連接酶c-Cbl介導的泛素化。此外，USP24的低下可抑制PD-1介導的免疫抑制作用，並且Usp24C1695A酵素失活突變減緩了EgfrL858R基因轉殖鼠誘導的肺腫瘤生成。值得注意的是，腫瘤微環境中升高的IL-6可活化 NF-κB/STAT3 訊號傳遞，並轉錄上調 USP24 表達，從而穩定 PD-1蛋白；相反地，中和IL-6降低USP24表現量並減少PD-1蛋白穩定性。此外，USP24特異性抑制劑USP24-i-101可促進T細胞對癌細胞毒性活性，抑制肺腫瘤生長，並在與 anti-CTLA4 免疫治療合併使用，達到更佳的抑癌效果。臨床上，肺癌患者若其腫瘤浸潤T細胞或周邊血T淋巴球中USP24表達量較高，則表現出明顯的T細胞耗竭特徵，並且對免疫療法反應較差。
結論：本研究解析了腫瘤浸潤 CD8+ T 細胞中去泛素化酵素 USP24 受IL-6/STAT3 活化而增強PD-1蛋白穩定性的調控機制，並揭示USP24可作為腫瘤免疫治療的潛在標靶。

Background: Persist programmed cell death-1 (PD-1)/PD-L1 inhibitory signaling impairs T cell cytotoxic function and eventually leads to T cell exhaustion. This process is strongly correlated with advanced cancer progression and the failure of immunotherapy. However, the mechanism governing PD-1 deubiquitination and T-cell dysfunction remains unclear. By dataset analysis, ubiquitin-specific peptidase 24 (USP24) has been found to be strongly associated with T cell dysfunction and poor responses to immunotherapy. However, it remains unclear whether upregulated USP24 in the tumor microenvironment contributes to PD-1 protein abundance.
Purpose: This study aims to investigate whether USP24 functions as a PD-1 deubiquitinase, thereby increasing PD-1 stability and contributing to T cell dysfunction and poor immunotherapy efficacy. Additionally, we further dissect the upstream regulatory mechanism controlling USP24 expression in T cells and its potential for cancer treatment.
Results: We observed that overexpression of USP24 strongly upregulated PD-1 protein expression with increased protein stability in T cells. Immunoprecipitation-Western blot assays confirmed that USP24 directly interacted with PD-1 and counteracted with the E3 ligase c-Cbl-mediated ubiquitination. Moreover, USP24 deficiency suppressed PD-1-mediated immunosuppression and attenuated EgfrL858R driven-lung tumorigenesis in Usp24C1695A-catalytic deficient mice. Notably, increased IL-6 level in the tumor microenvironment activated the NF-B/STAT3 signal and transcriptionally upregulated USP24 expression, which led to PD-1 stabilization. In contrast, IL-6 neutralization attenuated USP24 expression and PD-1 abundance. Targeting PD-1 stability with the USP24-specific inhibitor, USP24-i-101, boosted cytotoxic T-cell activity, restrained lung tumor growth, and achieved superior therapeutic effects when combined with anti-CTLA4 immunotherapy. Clinically, lung cancer patients with high USP24 expression in either tumor-infiltrating lymphocytes or peripheral T cells display exhausted features and show unfavorable responses to immunotherapy in lung cancer patients.
Conclusions: Our findings dissect the mechanism by which the deubiquitinase USP24, activated by IL-6/STAT3, enhances PD-1 protein stability and suppresses T cell anti-tumor response. Moreover, we identify USP24 as a potential target of anti-tumor immunotherapy.

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