ICAM1high Neutrophils Sculpt Tumor Evolution and Metastasis through Symbiotic Adhesion and Reverse Migration

Analyses of neutrophils of pan human cancers revealed a ICAM1high subset enriched in the tumor microenvironment, Murine triple negative breast cancer (TNBC) models recapitulate this observation. ICAM1high neutrophils exhibited enhanced capacity of cell-cell adhesion specifically with tumor cells retaining epithelial features, and this adhesion confers mutual advantages on both cell types. In contrast, cancer cells of mesenchymal-like phenotypes are thwarted by neutrophils due to decreased cell adhesion and elastase resistance. These nearly opposite effects drive the evolution toward a dichotomy of neutrophil-enriched, epithelial-like versus macrophage-enriched, mesenchymal-like ecosystems. The ICAM1high neutrophils are known for reverse migration (from tissue to circulation). The adhesive and reverse migratory properties together mediate metastatic intravasation. These observations were verified in a subset of human TNBCs that unexpectedly enrich non-Hispanic European patients. Thus, we demonstrated a co-evolution through which neutrophils sculpt phenotypes and metastatic behaviors of TNBC, which may preferentially occur in patients of certain race/ethnicity.