Abstract
Neutrophils are the first leukocytes recruited to sites of inflammation, where they execute anti-microbial functions to eliminate infectious agents. These functions include phagocytosis, release of reactive oxygen species and the formation of neutrophil extracellular traps via NETosis. Neutrophils are receiving increasing attention in the context of cancer, where these same neutrophil-associated functions are also important for modulating tumor growth and metastatic progression. Neutrophils are phenotypically heterogeneous and, depending on the context, exert anti- or pro-tumorigenic functions. Increasing evidence also suggests an important role of neutrophils and their involvement in promoting multiple steps of the metastatic cascade. The steps include: (1) local invasion and intravasation of cancer cells into circulation, (2) survival of cancer cells in the bloodstream and extravasation at a distant site, (3) early cancer cell seeding/survival, and (4) progressive growth of cancer cells to form macroscopic metastases. Although neutrophil functions designed to eliminate infectious agents can also eliminate tumor cells, their dysregulation can promote tumor growth and enable metastasis at multiple steps along the metastatic cascade. In this review, we will provide an overview of the current advances in neutrophil biology in the context of cancer. We also discuss the emerging field of immunometabolism, in which the rewiring of alternative metabolic pathways within neutrophils can impact their pro-tumorigenic/pro-metastatic functions.
Highlights
Neutrophils account for 50–70% of circulating leukocytes and are the first immune cells recruited to an inflammatory site
These results demonstrate that neutrophils can impair tumor growth and metastasis using a combination of direct and indirect cancer cell killing mechanisms (Supplementary Table 1)
NETosis is a process that involves the extrusion of neutrophil-derived chromatin structures that are decorated with neutrophil granule constituents, which form extracellular structures called neutrophil extracellular traps (NETs) [28]
Summary
Neutrophils account for 50–70% of circulating leukocytes and are the first immune cells recruited to an inflammatory site. It was demonstrated that expression of TRPM2 (transient receptor potential cation channel, subfamily M2) on tumor cells increased their sensitivity to neutrophil-mediated, H2O2-dependent, cytotoxicity This occurred through a mechanism that involved a transient increase in Ca2+ mobilization within cancer cells [18]. In early-stage human lung cancer, a subset of immature neutrophils have been identified as having antigen-presenting functions and act to promote anti-tumor immunity by stimulating the secretion of inflammatory cytokines from T lymphocytes [23]. IgA antibodies against receptors expressed by cancer cells (Her, EGFR) could enhance neutrophil-mediated trogocytosis of cancer cells if the CD47-SIRPα innate immune cell checkpoint was simultaneously blocked [26, 27] Taken together, these results demonstrate that neutrophils can impair tumor growth and metastasis using a combination of direct and indirect cancer cell killing mechanisms (Supplementary Table 1)
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