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

Analyses of neutrophils of pan human cancers revealed an ICAM1high subset enriched in the tumor microenvironment, mMurine 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 in 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.