Transcriptomic Signatures of Monocyte-Derived Macrophages Associate With Androgen Receptor Pathway Inhibitor Progression in Prostate Cancer.

BACKGROUND: Androgen receptor pathway inhibitors (ARPIs) have significantly improved clinical outcomes for patients with metastatic prostate cancer (PC) but acquired ARPI resistance remains universal. Maximizing ARPI treatment duration is crucial to optimal clinical outcomes, but current clinical tools to detect acquired ARPI resistance, including serum Prostate Specific Antigen (PSA) and radiographic disease monitoring, are limited in both sensitivity and specificity. Since prostate cancer disease progression is associated with an increase in systemic inflammation, we hypothesized that circulating monocytes and monocyte-derived macrophages (MDMs) in patients with PC would express an increased pro-inflammatory phenotype in the context of disease progression. METHODS: Monocytes and MDMs were isolated from peripheral blood samples from 16 patients with PC who were receiving ARPI therapies and performed transcriptomic and functional analysis both alone and in ex vivo coculture with prostate tumor cells utilizing a novel microscale coculture platform. RESULTS: We identified a pro-inflammatory transcriptional signature in MDMs cultured with tumor cells that was associated with current, recent, and impending disease progression. Furthermore, we found that the pro-inflammatory phenotype of MDMs derived from patients with clinical progression was associated with paracrine anti-tumorigenic signaling that sensitized tumor cells to ARPI treatment in vitro. Finally, a transcriptional score generated from the MDM transcriptional signature of progressing patients could accurately identify current treatment response status as well as patients with recent/impending changes in response status. CONCLUSIONS: Disease progression in patients with prostate cancer receiving ARPI therapy is associated with a pro-inflammatory gene signature in peripheral monocyte-derived macrophages. We were able to develop a scoring signature based on this pro-inflammatory gene signature that has the potential to identify patients with recent and impending changes in disease response status that is not detectable using conventional disease assessment criteria. Further research will be needed to validate these findings.