Blockade of colony-stimulating factor-1 receptor (CSF-1R) enables the therapeutic targeting of tumor-associated macrophages (TAM) in cancer patients. Various CSF-1R inhibitors, monoclonal antibodies and tyrosine kinase inhibitors, are currently evaluated in early clinical trials. Presence of an alternative survival signal such as GM-CSF rescues human monocyte-derived macrophages from CSF-1R inhibitor-induced apoptosis. In this study, we sought to identify additional factors which mediate resistance to CSF-1R-blocking antibody RG7155 (emactuzumab). We investigated the impact of hypoxia, macrophage-polarizing cytokines interleukin-4 (IL-4) and -10 (IL-10), and genetic alterations within the CSF1R locus and mitochondrial DNA. Among all investigated factors only IL-4 completely rescued viability of RG7155 treated macrophages in vitro. This RG7155-resistant population was characterized by a substantially increased mannose receptor-1 (CD206) expression. Analysis of CD206 and the hemoglobin scavenger receptor CD163 expression on normal tissue allowed for discrimination of distinct macrophage populations according to localization and frequency. In emactuzumab-treated cancer patients, we found a significant reduction of CSF-1R, CD204 and CD163 mRNA levels in contrast to a less pronounced decrease of CD206 expression by transcriptome analysis of tumor biopsies. However, we detected in normal skin tissue, which shows lower IL-4 mRNA expression compared to melanoma tissue, significant reduction of CD206+ dermal macrophages in RG7155 treated skin biopsies. These results suggest that in cancers where the cytokines IL-4 and GM-CSF are sufficiently expressed to induce very high CD206 expression on macrophages, CSF-1R inhibition may not deplete CD206hi TAM. This observation can help to identify those patients most likely to benefit from CSF-1R targeting agents.
- Received March 16, 2016.
- Revision received August 12, 2016.
- Accepted August 18, 2016.
- Copyright ©2016, American Association for Cancer Research.