Androgen receptor affects the response to immune checkpoint therapy by suppressing PD-L1 in hepatocellular carcinoma
Androgen receptor affects the response to immune checkpoint therapy by suppressing PD-L1 in hepatocellular carcinoma
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DOI：
10.18632/aging.103231
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发表时间：
2020-06-30
期刊：
影响因子：
5.2
通讯作者：
Cai, Xiujun
中科院分区：
文献类型：
--
作者：
Jiang, Guangyi;Shi, Liang;Cai, Xiujun
肝细胞癌（HCC）是一种异质性恶性肿瘤，在发病和病程上存在性别差异。雄激素受体（AR）是一种雄性激素受体，在肝癌的发生和发展中至关重要。AR在HCC中的作用已被机械表征，并且已开发出抗AR疗法，显示出有限的疗效。以免疫检查点蛋白为靶点的免疫治疗可能会大大改善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，我们证明了AR负调控PD-L1，作为PD-L1的转录抑制因子。值得注意的是，AR在HCC细胞中的过表达在体外增强了CD 8（+）T细胞功能。然后我们验证了患者中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PD-L1表达，可能导致HCC中的性别差异。更好地了解AR在HCC发生和发展过程中的作用将为开发潜在的HCC免疫治疗提供新的角度。
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 CD8(+)T function in vitro. 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.