TMEM160 promotes tumor immune evasion and radiotherapy resistance via PD-L1 binding in colorectal cancer

作者：Xiaofeng Dai, Zhipeng Wu, Ruiwen Ruan, Jingyi Chen, Chunye Huang, Wan Lei, Yangyang Yao, Li Li, Xiaomei Tang, Jianping Xiong, Miao Feng, Jun Deng · 发表于：Cell Communication and Signaling · 年份：2024 · DOI：10.1186/s12964-024-01541-w · 被引用次数：21 · 研究领域：Cancer Immunotherapy and Biomarkers、Ferroptosis and cancer prognosis、Cancer Cells and Metastasis

BACKGROUND: The effectiveness of anti-programmed cell death protein 1(PD-1)/programmed cell death 1 ligand 1(PD-L1) therapy in treating certain types of cancer is associated with the level of PD-L1. However, this relationship has not been observed in colorectal cancer (CRC), and the underlying regulatory mechanism of PD-L1 in CRC remains unclear. METHODS: Binding of TMEM160 to PD-L1 was determined by co-immunoprecipitation (Co-IP) and GST pull-down assay.The ubiquitination levels of PD-L1 were verified using the ubiquitination assay. Phenotypic experiments were conducted to assess the role of TMEM160 in CRC cells. Animal models were employed to investigate how TMEM160 contributes to tumor growth.The expression and clinical significance of TMEM160 and PD-L1 in CRC tissues were evaluated by immunohistochemistry(IHC). RESULTS: In our study, we made a discovery that TMEM160 interacts with PD-L1 and plays a role in stabilizing its expression within a CRC model. Furthermore, we demonstrated that TMEM160 hinders the ubiquitination-dependent degradation of PD-L1 by competing with SPOP for binding to PD-L1 in CRC cells. Regarding functionality, the absence of TMEM160 significantly inhibited the proliferation, invasion, metastasis, clonogenicity, and radioresistance of CRC cells, while simultaneously enhancing the cytotoxic effect of CD8 + T cells on tumor cells. Conversely, the upregulation of TMEM160 substantially increased these capabilities. In severely immunodeficient mice, tumor ...