The deubiquitinase USP2a promotes tumor immunosuppression by stabilizing immune checkpoint B7-H4 in lung adenocarcinoma harboring EGFR-activating mutants.

Autor: Lu Y; College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China., Sun Y; College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China., Zhang J; College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China., Kong M; College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China., Zhao Z; College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China., Sun B; College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China., Wang Y; College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China., Jiang Y; Department of Hematology, Shanghai Zhaxin Traditional Chinese and Western Medicine Hospital, Shanghai, China., Chen S; Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China., Wang C; Department of Gastroenterology, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, China., Tong Y; Department of Hematology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Wen L; He Cheng Biotechnology Suzhou Co.Ltd, Suzhou, Jiangsu, China., Huang M; Department of Bioinformatics, School of Biology & Basic Medical Sciences, Soochow University, Suzhou, China., Wu F; Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China. Electronic address: 1701823@tongji.edu.cn., Zhang L; College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China. Electronic address: zliang@suda.edu.cn.
Jazyk: angličtina
Zdroj: Cancer letters [Cancer Lett] 2024 Aug 01; Vol. 596, pp. 217020. Date of Electronic Publication: 2024 Jun 06.
DOI: 10.1016/j.canlet.2024.217020
Abstrakt: B7-H4 is an immune checkpoint crucial for inhibiting CD8 + T-cell activity. A clinical trial is underway to investigate B7-H4 as a potential immunotherapeutic agent. However, the regulatory mechanism of B7-H4 degradation via the ubiquitin-proteasome pathway (UPP) remains poorly understood. In this study, we discovered that proteasome inhibitors effectively increased B7-H4 expression, while EGFR-activating mutants promoted B7-H4 expression through the UPP. We screened B7-H4 binding proteins by co-immunoprecipitation and mass spectrometry and found that USP2a acted as a deubiquitinase of B7-H4 by removing K48- and K63-linked ubiquitin chains from B7-H4, leading to a reduction in B7-H4 degradation. EGFR mutants enhanced B7-H4 stability by upregulating USP2a expression. We further investigated the role of USP2a in tumor growth in vivo. Depletion of USP2a in L858R/LLC cells inhibited tumor cell proliferation, consequently suppressing tumor growth in immune-deficient nude mice by destabilizing downstream molecules such as Cyclin D1. In an immune-competent C57BL/6 mouse tumor model, USP2a abrogation facilitated infiltration of CD95 + CD8 + effector T cells and hindered infiltration of Tim-3+CD8 + and LAG-3+CD8 + exhausted T cells by destabilizing B7-H4. Clinical lung adenocarcinoma samples showed a significant correlation between B7-H4 abundance and USP2a expression, indicating the contribution of the EGFR/USP2a/B7-H4 axis to tumor immunosuppression. In summary, this study elucidates the dual effects of USP2a in tumor growth by stabilizing Cyclin D1, promoting tumor cell proliferation, and stabilizing B7-H4, contributing to tumor immunosuppression. Therefore, USP2a represents a potential target for tumor therapy.
Competing Interests: Declaration of competing interest The authors declare no competing interests.
(Copyright © 2024. Published by Elsevier B.V.)
Databáze: MEDLINE
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