Androgen Receptor Inhibition Increases MHC Class I Expression and Improves Immune Response in Prostate Cancer

Abstract Tumors escape immune detection and elimination through a variety of mechanisms. Here, we used prostate cancer as a model to examine how androgen-dependent tumors undergo immune evasion through downregulation of the major histocompatibility complex class I (MHCI). We report that response to immunotherapy in late-stage prostate cancer is associated with elevated MHC expression. To uncover the mechanism, we performed a genome-wide CRISPR interference (CRISPRi) screen and identified androgen receptor (AR) as a repressor of the MHCI pathway. Syngeneic mouse models of aggressive prostate cancer deficient in Ar also demonstrated increased tumor immunogenicity and promoted T cell–mediated tumor control. Notably, the increase in MHCI expression upon AR blockade is transient and correlates with resistance to AR inhibition. Mechanistic studies identified androgen response elements upstream of MHCI transcription start sites which increased MHCI expression when deleted. Together, this body of work highlights another mechanism by which hormones can promote immune escape. Significance: Immunotherapy options for immune cold tumors, like prostate cancer, are limited. We show that AR downregulates MHCI expression/antigen presentation and that AR inhibition improves T-cell responses and tumor control. This suggests that treatments combining AR inhibitors and checkpoint blockade may improve tumor immune surveillance and antitumor immunity in patients.