Cancer-promoting mechanisms of tumor-associated neutrophils

Neutrophils have classically been considered to mount a defensive response against tumor cells, yet recent evidence suggests tumors modulate neutrophil function to support tumor growth and progression. Tumor-associated neutrophils (TANs) are phenotypically distinct from circulating neutrophils in terms of their surface protein composition and cyto/chemokine activity and response. Although TANs have been shown to both promote and inhibit tumor advancement, the preponderant activity augments tumor progression. This review discusses these cancer-promoting molecular pathways, relevant diagnostic studies in patients, and subsequent treatment modalities. The tumor promoting mechanisms of TANs include dampening of CD8+ response via Arginase-1; a neutrophil-secreted neutrophil elastase (NE) upregulation of tumor cellular proliferation pathways; degradation of basement membrane and ECM via NE and MMP-9; upregulation of angiogenesis by VEGF, and HGF; and ICAM-1 dependent tumor intravasation, immune protection in circulation, and extravasation into distant, metastatic tissue beds. Clinicians are constrained in treating TANs systemically as it may induce neutropenia, therefore targeting TANs-mediated tumor progression pathways surgically on a loco-regional level is a viable adjuvant treatment modality. TANs modulate the tumor microenvironment promoting tumor progression. Mechanistic understanding of TANs role in tumor progression will provide unique therapeutic alternatives. •A phenotypically distinct population of neutrophils, called Tumor Associated Neutrophils (TANs) have been shown to be recruited into solid tumors, where the functions of TANs is modified and coapted to aid in tumor progression.•This review focuses on these mechanisms mediating cancer progression and then discusses the potential role of surgically-based adjuvant therapy in loco-regional targeting of these pro-cancer mechanisms.