Androgen Receptor Transcriptionally Inhibits Programmed Death Ligand-1 Expression and Influences Immune Escape in Bladder Cancer

In multiple clinical trials, immune checkpoint blockade-based immunotherapy has shown sig- nificant therapeutic efficacy in bladder cancer (BCa). Sex is closely related to the incidence rate and prognosis of BCa. As one of the sex hormone receptors, the androgen receptor (AR) is a well-known key regulator that promotes the progression of BCa. However, the regulatory mechanism of AR in the immune response of BCa is still unclear. In this study, the expression of AR and programmed death ligand 1 (PD-L1) was negatively correlated in BCa cells, clinical tissues, and tumor data extracted from the Cancer Genome Atlas Bladder Urothelial Carcinoma cohort. A human BCa cell line was transfected to alter the expression of AR. The results show that AR negatively regulated PD-L1 expression by directly binding to AR response elements on the PD-L1 promoter region. In addition, AR overexpression in BCa cells significantly enhanced the antitumor activity of cocul- tured CD8 thorn T cells. Injection of anti-PD-L1 monoclonal antibodies into C3H/HeN mice signifi- cantly suppressed tumor growth, and stable expression of AR dramatically enhanced the antitumor activity in vivo. In conclusion, this study describes a novel role of AR in regulating the immune response to BCa by targeting PD-L1, thus providing potential therapeutic strategies for immunotherapy in BCa.(c) 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.