Research Paper Volume 12, Issue 12 pp 11466—11484
Androgen receptor affects the response to immune checkpoint therapy by suppressing PD-L1 in hepatocellular carcinoma
- 1 Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- 2 Key Laboratory of Laparoscopic Technology of Zhejiang Province, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
Received: November 16, 2019 Accepted: March 29, 2020 Published: June 24, 2020https://doi.org/10.18632/aging.103231
How to Cite
Copyright © 2020 Jiang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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.
AR: androgen receptor; ARE: antioxidant response element; ChIP: chromatin immunoprecipitation assay; HCC: hepatocellular carcinoma; PD-1: programmed cell death protein 1; PD-L1: programmed death-ligand 1; PI: propidium Iodide; CSFE: carboxyfluorescein diacetate, succinimidyl ester; WT: wild type; TILs: tumor infiltrating lymphocytes.