LAUSR

Neutrophils are short-lived immune cells whose main function is to mediate antimicrobial host defense. To function effectively, neutrophils must sense microbial products and host-derived cytokines and chemokines, traffic to sites of infection and injury, and kill pathogens. Neutrophils contain a broad armamentarium of antimicrobial products, many of which are sequestered in granules and activated by infection and mimics of infection (e.g. bacterial cell wall products). In addition to microbial products, neutrophils can be activated by damage-associated molecular patterns (DAMPs) (1–4), which are endogenous danger signals that are released from damaged or necrotic cells and activate the innate immune system by engaging pattern recognition receptors (PRRs). However, the same pathways that kill pathogens and amplify inflammation can also cause injury to the host. Neutrophil extracellular traps (NETs) are extracellular chromatin and granular constituents that are generated in response to microbial and damage motifs, and target extracellular pathogens, but are also pro-thrombotic and injurious (5). The research of the role of “Neutrophils in Cancer”, the theme of this Research Topic, has emerged substantially during the last decade. A major theme of this Research Topic, relates to how antimicrobial pathways in neutrophils are activated by DAMPs and cytokine signals in the tumor microenvironment (TME) in ways that can promote or restrict tumor progression. Tumor-associated neutrophils are reprogrammed by cues in the TME, and, in turn, can cross-signal to tumor cells and reshape the immune landscape of the TME. These signaling interactions driven by neutrophils are potential targets for immunotherapy. A number of studies show that tumor-infiltrating granulocytic cells are negative prognostic biomarkers. Gentles at al. (6) analyzed expression signatures from ~18,000 human tumors with overall survival outcomes across 39 malignancies, and identified intra-tumoral neutrophil signatures as the most significant adverse cancer-wide prognostic marker. Si et al. (7) noted intra-tumoral hotspots for co-localization of granulocytic and T cells in primary head and neck tumors, where a subset of granulocytes expressing LOX-1 and arginase I correlated with reduced activation of adjacent T cells. The TME can influence neutrophil biology at multiple levels. Tumor-derived factors (e.g., G-CSF or GM-CSF) can drive abnormal myelopoiesis skewed toward granulocytic differentiation. Disordered myelopoiesis is a central mechanism for expansion of myeloid-derived suppressor cells (MDSC) in