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.

中文翻译：

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EPDR1 通过抑制 IkappaB 激酶-β的 TRIM21 依赖性泛素化来促进 PD-L1 表达和肿瘤免疫逃逸。


虽然免疫检查点阻断 （ICB） 已显示出临床癌症治疗的前景，但其疗效仅在有限一部分患者中观察到，并且调节肿瘤细胞对 ICB 的先天性和获得性耐药的潜在机制仍然知之甚少。在这里，我们确定室管膜相关蛋白 1 （EPDR1） 是 PD-L1 表达和肿瘤免疫逃避的重要肿瘤内在调节因子。EPDR1 在肝细胞癌中的异常表达与免疫抑制有关。从机制上讲，EPDR1 与 E3 连接酶 TRIM21 结合并破坏其与 IkappaB 激酶-b 的相互作用，抑制其泛素化和自噬体降解，并增强 NF-κB 介导的 PD-L1 转录激活。此外，我们通过小鼠肝癌模型验证了 EPDR1 介导 CD8+ T 细胞耗竭并促进肿瘤进展。此外，我们在人和小鼠肝癌样本中观察到 EPDR1 和 PD-L1 表达呈正相关。总的来说，我们的研究揭示了 EPDR1 在协调肿瘤免疫逃逸和癌症进展中以前未被重视的作用。