Enzalutamide, an Androgen Receptor Antagonist, Enhances Myeloid Cell–Mediated Immune Suppression and Tumor Progression

Androgen receptor (AR) antagonism increases overall survival in prostate cancer; however, treatment failure leads to tumor progression and patient mortality. The effect of AR modulation on AR+ non-tumor cells that participate in the resistance to AR antagonism is poorly understood. Tumor-infiltrating myeloid cells, including macrophages and myeloid-derived suppressor cells (MDSCs), express AR and promote prostate cancer progression. We investigated how AR antagonism affects myeloid cell function and metabolism in an AR-independent murine colon tumor model. Systemic blockade of AR with enzalutamide resulted in increased MC-38 tumor growth in vivo even when AR was knocked out of MC-38 tumor cells. MC-38 tumor growth was also increased when immunocompetent, but not immuno-deficient, mice were co-injected with tumor cells and MDSCs treated with enzalutamide or lacking AR, suggesting that AR regulated the ability of MDSCs to suppress adaptive immunity. Myeloid AR knockout (MARKO) male mice also displayed increased growth of TRAMP C2 prostate tumors when compared to WT. Inhibition of AR signaling suppressed mitochondrial respiration in myeloid cells via MPC/AMPK signaling pathways; suppression of mitochondrial respiration increased MDSC tumor-promoting functions. Our work showed that AR regulates a tumor-promoting myeloid cell phenotype and influences myeloid cell metabolism. These findings suggest that tumor resistance to AR antagonism is due in part to changes in myeloid cell function and metabolism.