2. Academic Validation
  3. EPDR1 promotes PD-L1 expression and tumor immune evasion by inhibiting TRIM21-dependent ubiquitylation of IkappaB kinase-β

EPDR1 promotes PD-L1 expression and tumor immune evasion by inhibiting TRIM21-dependent ubiquitylation of IkappaB kinase-β

  • EMBO J. 2024 Aug 16. doi: 10.1038/s44318-024-00201-6.
Xiaoyu Qian # 1,  Jin Cai # 1,  Yi Zhang 1,  Shengqi Shen 2,  Mingjie Wang 1,  Shengzhi Liu 1,  Xiang Meng 1,  Junjiao Zhang 1,  Zijian Ye 1,  Shiqiao Qiu 1,  Xiuying Zhong 3,  Ping Gao 4 5
Affiliations

Affiliations

  • 1 School of Medicine, South China University of Technology, Guangzhou, China.
  • 2 Medical Research Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China.
  • 3 Medical Research Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China. zxywawj@ustc.edu.cn.
  • 4 School of Medicine, South China University of Technology, Guangzhou, China. pgao2@ustc.edu.cn.
  • 5 Medical Research Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China. pgao2@ustc.edu.cn.
  • # Contributed equally.
PMID: 39152265 DOI: 10.1038/s44318-024-00201-6
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.

Keywords

EPDR1; Hepatocellular Carcinoma; TRIM21; Tumor Immune Evasion.

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