1. EPDR1 promotes PD-L1 expression and tumor immune evasion by inhibiting TRIM21-dependent ubiquitylation of IkappaB kinase-β.
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Qian, Xiaoyu, Cai, Jin, Zhang, Yi, Shen, Shengqi, Wang, Mingjie, Liu, Shengzhi, Meng, Xiang, Zhang, Junjiao, Ye, Zijian, Qiu, Shiqiao, Zhong, Xiuying, and Gao, Ping
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T-cell exhaustion ,IMMUNE checkpoint proteins ,UBIQUITIN ligases ,LIVER cancer ,NATURAL immunity - Abstract
While immune checkpoint blockade (ICB) has shown promise for clinical cancer therapy, its efficacy has only been observed in a limited subset of patients and the underlying mechanisms regulating innate and acquired resistance to ICB of tumor cells remain poorly understood. Here, we identified ependymin-related protein 1 (EPDR1) as an important tumor-intrinsic regulator of PD-L1 expression and tumor immune evasion. Aberrant expression of EPDR1 in hepatocellular carcinoma is associated with immunosuppression. Mechanistically, EPDR1 binds to E3 ligase TRIM21 and disrupts its interaction with IkappaB kinase-b, suppressing its ubiquitylation and autophagosomal degradation and enhancing NF-κB-mediated transcriptional activation of PD-L1. Further, we validated through a mouse liver cancer model that EPDR1 mediates exhaustion of CD8
+ T cells and promotes tumor progression. In addition, we observed a positive correlation between EPDR1 and PD-L1 expression in both human and mouse liver cancer samples. Collectively, our study reveals a previously unappreciated role of EPDR1 in orchestrating tumor immune evasion and cancer progression. Synopsis: PD-L1 is a key immune checkpoint and largely affects the response of patients to immunotherapy. This study identifies ependymin-related protein 1 (EPDR1) as a potent regulator of PD-L1 expression in hepatocellular carcinoma (HCC), facilitating immune evasion. Aberrant expression of EPDR1 in HCC is associated with immunosuppression. Tumor-intrinsic EPDR1 facilitates immune evasion by increasing anti-tumor CD8 + T cells exhaustion. EPDR1 enhances the NF-κB pathway and elevates PD-L1 expression in cancer cells by interfering with TRIM21-dependent degradation of IkappaB kinase-b. EPDR1-TRIM21-PD-L1 axis promotes tumor immune evasion in HCC. A tumor-intrinsic EPDR1-TRIM21-PD-L1 axis promotes CD8 + T cells exhaustion in liver cancer. [ABSTRACT FROM AUTHOR]- Published
- 2024
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