CSF-1R Mediated Inhibition of Alternatively Activated Macrophages to Augment Androgen Receptor Blockade Therapy
Authors:
Jemima Escamilla, Connie LiuMentor:
Lily Wu, Professor, University of California Los AngelesTraditional means of treating prostate cancer (PCa) is through androgen receptor (AR) blockade therapy. However, AR blockade therapy acquires resistance over time. Various reports show that androgen deprivation results in increased inflammatory response in PCa and suggest potential roles of inflammatory cells, such as macrophages, in the acquisition of castration-resistant prostate cancer (CRPC). Macrophages have been shown to be important for growth factor secretion and increased angiogenesis. It has been shown that colony stimulating factor 1 receptor (CSF-1R) signaling is important for the recruitment of tumor-associated macrophages (TAMs). We hypothesized that inhibition of recruitment of TAMs with a CSF-1R inhibitor; Plexikkon in combination with AR blockade therapy would have synergistic results in CRPC. We observed that AR blockade therapy resulted in increased CSF-1 expression in castrated tumors, which correlates with increased macrophage infiltration. Plexikkon treatment significantly reduced macrophage infiltration in these tumors and subsequently reduced CSF-1 expression. We also observed decreased transcript expression of VEGF-A and MMP-9, pro-tumor markers with the treatment. In addition, immunohistochemistry tumor tissue stains showed decrease in functional blood vasculature. Growth factor expression of IGF-1 was significantly reduced with the combination treatment, suggesting slower proliferation of cells. These results suggest that TAMs in the tumor microenvironment contribute to PCa progression and therapeutic resistance.