The Multifaceted Role of Androgen Receptor Signaling in Immunity: Implications for Oncology.

Abstract

Whereas the androgen receptor (AR) is canonically known for its role in the prostate and testis, AR signaling exerts broad immunomodulatory effects through direct and indirect signaling in multiple immune cell compartments and contributes significantly to sex differences in autoimmunity, infection, and cancer. Mouse model perturbations of androgen signaling through castration, testicular feminization, and cell type-specific Ar knockout have provided important insights into cell-intrinsic and -extrinsic mechanisms by which AR signaling affects innate and adaptive immunity. However, the precise molecular underpinnings of these effects remain largely unknown. Moreover, despite convincing epidemiologic and correlative observations that highlight the importance of AR signaling in human immune function, it remains unclear how reliably findings in mice will translate to humans. A better understanding of how to augment immune function through androgen signaling modulation could have significant clinical relevance for the treatment of cancer, as well as other disease states involving immune dysregulation. In this review, we discuss the current evidence for the functional effects of AR signaling within the major immune cell compartments of the innate and adaptive immune systems. We also review ongoing clinical efforts that modify AR signaling for the purpose of enhancing antitumor immunity.