Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
Key Laboratory of Laparoscopic Technology of Zhejiang Province, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
Aging (Albany NY). 2020 Jun 24;12(12):11466-11484. doi: 10.18632/aging.103231.
Hepatocellular carcinoma (HCC) is a heterogeneous malignancy with gender-related differences in onset and course. Androgen receptor (AR), a male hormone receptor, is critical in the initiation and progression of HCC. The role of AR in HCC has been mechanistically characterized and anti-AR therapies have been developed, showing limited efficacy. Immunotherapy targeting immune checkpoint proteins may substantially improve the clinical management of HCC. The mechanism by which AR influences HCC immune state remains unclear. In this study, we demonstrated that AR negatively regulated PD-L1, by acting as a transcriptional repressor of PD-L1. Notably, AR over-expression in HCC cells enhanced CD8T function . We then verified the AR/PD-L1 correlation in patients. In animal experiment we found that lower AR expressed tumor achieved better response to PD-L1 inhibitor. Thus, AR suppressed PD-L1 expression, possibly contributing to gender disparity in HCC. Better understanding of the roles of AR during HCC initiation and progression will provide a novel angle to develop potential HCC immunotherapies.
肝细胞癌（HCC）是一种具有性别相关差异的异质性恶性肿瘤，其发病和病程存在性别差异。雄激素受体（AR）是一种男性激素受体，在 HCC 的发生和进展中起着关键作用。AR 在 HCC 中的作用已从机制上得到了描述，并且已经开发了抗 AR 治疗方法，但疗效有限。针对免疫检查点蛋白的免疫疗法可能会极大地改善 HCC 的临床管理。AR 影响 HCC 免疫状态的机制尚不清楚。在这项研究中，我们证明 AR 通过作为 PD-L1 的转录抑制剂来负调控 PD-L1。值得注意的是，HCC 细胞中 AR 的过表达增强了 CD8T 功能。然后，我们在患者中验证了 AR/PD-L1 的相关性。在动物实验中，我们发现 AR 表达较低的肿瘤对 PD-L1 抑制剂的反应更好。因此，AR 抑制了 PD-L1 的表达，这可能导致 HCC 中的性别差异。更好地了解 AR 在 HCC 发生和进展过程中的作用，将为开发潜在的 HCC 免疫疗法提供新的角度。
