The tumor-neutrophil interactions in the microenvironment of brain metastases with different primary sites.

Brain metastases (BrM) originating from lung and breast cancer can recruit and activate neutrophils to acquire a tumor-promoting phenotype. It is currently unclear if this phenomenon also occurs in BrM arising from other primary sites. Here, we investigated the effect of tumor cells isolated from melanoma, lung and gastrointestinal (GI) cancer BrM on neutrophil biology and functions. We found that lung and GI, but not melanoma BrM cells produced CXCL8/IL-8, and promoted neutrophil recruitment. Similarly, lung and GI, but not melanoma BrM cells, prolonged the survival of neutrophils, and stimulated them to release MMP9 and CCL4/MIP1β. In situ, lung and GI BrM tissues contained significantly higher numbers of tumor-infiltrating neutrophils compared to melanoma BrM. The levels of neutrophil infiltration significantly correlated with the proliferation index of these tumors. Our findings identify variabilities in the immune microenvironment of BrM with different primary sites, which may ultimately affect their pathophysiology and progression.