ISG15 targets glycosylated PD-L1 and promotes its degradation to enhance antitumor immune effects in lung adenocarcinoma

作者：Tongyuan Qu, Wenshuai Zhang, Chenhui Yan, Danyang Ren, Yalei Wang, Yuhong Guo, Qianru Guo, Jinpeng Wang, Liren Liu, Lei Han, Lingmei Li, Qiujuan Huang, Lu Cao, Zhaoxiang Ye, Bin Zhang, Qiang Zhao, Wenfeng Cao · 发表于：Journal of Translational Medicine · 年份：2023 · DOI：10.1186/s12967-023-04135-1 · 被引用次数：42 · 研究领域：Cancer Immunotherapy and Biomarkers、interferon and immune responses、Ferroptosis and cancer prognosis

BACKGROUND: Immunocheckpoint inhibitors (ICIs) have been widely used in the clinical treatment of lung cancer. Although clinical studies and trials have shown that patients can benefit significantly after PD-1/PD-L1 blocking therapy, less than 20% of patients can benefit from ICIs therapy due to tumor heterogeneity and the complexity of immune microenvironment. Several recent studies have explored the immunosuppression of PD-L1 expression and activity by post-translational regulation. Our published articles demonstrate that ISG15 inhibits lung adenocarcinoma progression. Whether ISG15 can enhance the efficacy of ICIs by modulating PD-L1 remains unknown. METHODS: The relationship between ISG15 and lymphocyte infiltration was identified by IHC. The effects of ISG15 on tumor cells and T lymphocytes were assessed using RT-qPCR and Western Blot and in vivo experiments. The underlying mechanism of PD-L1 post-translational modification by ISG15 was revealed by Western blot, RT-qPCR, flow cytometry, and Co-IP. Finally, we performed validation in C57 mice as well as in lung adenocarcinoma tissues. RESULTS: T cell proliferation and invalidity and immune responses against tumors. Mechanistically, we demonstrated that the ubiquitination-like modifying effect of ISG15 on PD-L1 increased the modification of K48-linked ubiquitin chains thus increasing the degradation rate of glycosylated PD-L1 targeting proteasomal pathway. The expression of ISG15 and PD-L1 was negatively correlated in NSCL...