Compensatory Csf2-driven macrophage activation blunts long-term efficacy of therapeutic Csf1r inhibition in breast-to-brain metastasis

Tumor microenvironment-targeted therapies are emerging as promising treatment options for different tumor types. Tumor-associated macrophages/microglia (TAMs) represent the most abundant non-malignant cell type in brain metastasis and are known to support metastatic colonization and outgrowth. We used the colony-stimulating factor 1 receptor (Csf1r) inhibitor BLZ945 to target TAMs at distinct stages of the metastatic cascade in experimental breast-to-brain metastasis and demonstrate that Csf1r inhibition leads to anti-tumor responses in prevention and intervention trails. However, compensatory Csf2-mediated pro-inflammatory TAM activation blunts long-term efficacy of Csf1r inhibition by inducing signatures associated with neuroinflammation followed by wound repair responses that foster tumor recurrence. Combined blockade of Csf1r and Csf2rb-Stat5 signaling leads to sustained tumor control and a normalization of microglial activation states. Overall design: Microglia (MG), monocyte-derived macrophages (MDM) and MDA brain metastasis (BrM) GFP+ tumor cells were FAC-sorted from mice under the following conditions: healthy animals (n=3), BrM bearing, vehicle treated mice (n=5) and BrM bearing, BLZ945 treated mice (n=4). RNA was isolated and subjected to RNA-sequencing to investigate the education of MG and MDM in BrM and the consequences of Csf1r-targeted therapy.