Patients with prostate cancer respond poorly to checkpoint blockade immunotherapy (CBI). Guan and colleagues found that this resulted from androgen receptor (AR) activity impacting T-cell responses. Single-cell RNA sequencing was done on patients with metastatic castration-resistant prostate cancer that progressed on enzalutamide (AR antagonist) and subsequently received anti-PD1 CBI. Comparing differences in CD8+ T-cell gene expression in CBI responders versus nonresponders identified AR as a key transcription factor active in nonresponders. Using mouse models of prostate cancer, the authors showed that anti-PDL1 CBI was effective only when combined with androgen deprivation and AR antagonists. The therapy was independent of AR activity in tumors but required CD8+ T cells that exhibited enhanced activity with AR inhibition or genetic AR deficiency. Mechanistically, AR was found to bind regulatory elements in T-cell effector genes (e.g., IFNG and GZMB), reducing their expression.

Expert Commentary: Androgen deprivation and androgen receptor antagonism acts...

You do not currently have access to this content.