Androgen-mediated TGFβ expression suppresses anti-tumor neutrophil response in bone metastatic prostate cancer

Abstract

Prostate Cancer (PCa) bone metastasis is associated with spinal cord compression, fracture, bone pain and death. Despite advances in the androgen-targeted therapy for localized disease, metastatic disease is incurable and osseous progression is largely dictated by tumor-stromal interactions in the bone microenvironment. We showed previously that tumor bone neutrophils inhibit PCa but lose their cytotoxic potential as the tumor progresses. However, there have been no studies to date to clinically define and characterize neutrophils throughout prostate cancer and determine their biomarker potential. Using patient peripheral blood polymorphonuclear neutrophils (PMNs), we identify that PCa progression dictates PMN properties, including viability, cell surface markers and gene expression. However, the majority of PMNs elicited an anti-tumor ex vivo response demonstrating that PMN cytotoxicity is independent of PCa disease stage. In fact, we identified a novel role for androgen regulation, i.e., androgen deprivation therapy (ADT), in suppressing PMN cytotoxicity via altered transforming growth factor beta receptor I (TβRI). Using preclinical therapeutic trials, we found that high dose testosterone/bipolar androgen therapy (BAT) and genetic or pharmacologic TβRI inhibition combined with standard ADT rescued the androgen-associated suppression and restored PMN anti-tumor immune response. This combination provided a therapeutic strategy more impactful than ADT alone, in bone metastatic prostate cancer (BM-PCa). These studies: 1) highlight a necessity for both molecular and functional characterization of PMNs per cancer type and 2) reveals the ability to leverage PMN immune response for successful targeting of BM-PCa.