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

Brain metastases 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 brain metastases arising from other primary sites. Here, we investigated the effect of tumor cells isolated from melanoma, lung cancer, and gastrointestinal cancer brain metastases on neutrophil biology and functions. We found that lung and gastrointestinal but not melanoma brain metastasis cells produced CXCL8/IL-8 and promoted neutrophil recruitment. Similarly, lung and gastrointestinal but not melanoma brain metastasis cells prolonged the survival of neutrophils and stimulated them to release MMP9 and CCL4/MIP1 beta. In situ, lung and gastrointestinal brain metastasis tissues contained significantly higher numbers of tumor-infiltrating neutrophils compared to melanoma brain metastases. The levels of neutrophil infiltration significantly correlated with the proliferation index of these tumors. Our findings identify variabilities in the immune microenvironment of brain metastases with different primary sites, which may ultimately affect their pathophysiology and progression. The tumor-neutrophil interactions in brain metastases are dependent on the histologic origins of these tumors and may differentially affect tumor proliferation and progression.