Abstract
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.
Highlights
Hepatocellular carcinoma (HCC) is the sixth most common malignant tumor in the world
In an attempt to verify whether Androgen receptor (AR) influenced immune checkpoint protein expression in HCC, we evaluated the impact of different AR expression levels on Programmed death ligand-1 (PD-L1) expression in various HCC cell lines
RT-qPCR showed that overexpression AR attenuated PD-L1 mRNA expression and knockdown AR increased PD-L1 mRNA expression in HCC cell lines (Figure 1A)
Summary
Hepatocellular carcinoma (HCC) is the sixth most common malignant tumor in the world. HCC is characterized by gender disparity, with a 2:1 to 7:1 male-to-female ratio in disease incidence [6]. AR was first identified as a tumor-promoting gene in prostate cancer. Since AR is implicated in all stages of prostate cancer, AR antagonists have been developed for AR-targeted therapy [8–10]. In 2012, an AR inhibitor was approved by FDA for prostate cancer and yielded promising results [11]. In line with the observed gender disparity of the disease, AR contributes to the initiation and progression of HCC [12–14]. AR was identified as a therapeutic target for HCC [13]. The results of early clinical trials testing anti-androgen therapies in liver cancer were disappointing [15, 16]
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