CSF1 Receptor Targeting in Prostate Cancer Reverses Macrophage-Mediated Resistance to Androgen Blockade Therapy

Abstract

Growing evidence suggests that tumor-associated macrophages (TAMs) promote cancer progression and therapeutic resistance by enhancing angiogenesis, matrix-remodeling and immunosuppression. In this study prostate cancer (PCa) under androgen blockade therapy (ABT) was investigated, demonstrating that TAMs contribute to PCa disease recurrence through paracrine signaling processes. ABT induced the tumor cells to express macrophage colony-stimulating factor 1 (M-CSF-1 or CSF-1) and other cytokines that recruit and modulate macrophages, causing a significant increase in TAM infiltration. Inhibitors of CSF-1 signaling through its receptor, CSF-1R, were tested in combination with ABT, demonstrating that blockade of TAM influx in this setting disrupts tumor promotion and sustains a more durable therapeutic response compared to ABT alone.

Complex interplay between tumor microenvironment and cancer therapy

“…A growing body of evidence suggests that macrophages in TME are critical in promoting ADT resistance. For example, large numbers of TAMs were recruited to the TME shortly after ADT [109][110][111]. Moreover, the TAMs recruitment is associated with an increase in cancer cell proliferation [111,112].…”

The Selective Tie2 Inhibitor Rebastinib Blocks Recruitment and Function of Tie2Hi Macrophages in Breast Cancer and Pancreatic Neuroendocrine Tumors

“…In particular, tumor-associated macrophages (TAMs) not only promote cancer growth, cancer cell survival and motility (7,19–23), but can limit the efficacy of the tumor response to chemotherapy or radiotherapy (24–28). Tie2 + macrophages are known to be pro-angiogenic, pro-metastatic, and immunosuppressive in the tumor microenvironment (2,15,22,29).…”

The role of the tumour microenvironment in immunotherapy

“…In anaplastic thyroid cancer, expression of CD163, a marker for M2 macrophages, correlated with CXCR4 expression and more aggressive clinical characteristics . The potentially CXCR4-mediated recruitment of macrophages could be countered by CXCR4 inhibitors or by ablation of macrophages from the tumour microenvironment via CSF-1R depleting antibodies (Ries et al 2014, Escamilla et al 2015. Such compounds are currently in early clinical development by several companies.…”