Androgen receptor targeted therapy sensitizes tumor bearing mice to effective immunotherapy

Abstract

Abstract Sex hormones impact both the innate and adaptive immune response, contributing to differences in autoimmune diseases, response to infection, and cancer incidence between males and females. Androgens are known to exert a general immunosuppressive effect. Historically, immune checkpoint blockade (ICB) has not proven to be efficacious in patients with prostate cancer despite standard of care consisting of androgen deprivation therapy (ADT). Upon disease progression, men will be treated with second line ADT therapy; some of which can prevent androgen receptor transcriptional activity. One such drug is enzalutamide. Given T cells express AR, we hypothesized that enzalutamide treatment would relieve the immunosuppressive effects of androgens on T cells, rendering them more responsive to immunotherapy. In the studies presented, we sensitize castration resistant prostate cancer tumor bearing mice to effective ICB with a combination of castration and enzalutamide. This combination therapy leads to ~40% tumor rejection and long-term survival; an effect that is dependent on CD8 T cells. These tumor infiltrating CD8 T cells made 6-fold more IFNγ within the tumor in the triple therapy group compared to control group. Surprisingly, this combination therapy showed efficacy in the androgen independent sarcoma tumor model MCA-205. Using in vitro and in vivo assays, we show that enzalutamide has a direct effect on T cell function. Taken together, our data suggests that ADT, and specifically enzalutamide treatment, can sensitize tumor bearing animals to effective immune checkpoint blockade and allow for tumor control by T cells.