Abstract
The role of neutrophils in solid tumor metastasis remains largely controversial. In preclinical models of solid tumors, both pro-metastatic and anti-metastatic effects of neutrophils have been reported. In this study, using mouse models of breast cancer, we demonstrate that the metastasis-modulating effects of neutrophils are dictated by the status of host natural killer (NK) cells. In NK cell-deficient mice, granulocyte colony-stimulating factor-expanded neutrophils show an inhibitory effect on the metastatic colonization of breast tumor cells in the lung. In contrast, in NK cell-competent mice, neutrophils facilitate metastatic colonization in the same tumor models. In an ex vivo neutrophil-NK cell-tumor cell tri-cell co-culture system, neutrophils are shown to potentially suppress the tumoricidal activity of NK cells, while neutrophils themselves are tumoricidal. Intriguingly, these two modulatory effects by neutrophils are both mediated by reactive oxygen species. Collectively, the absence or presence of NK cells, governs the net tumor-modulatory effects of neutrophils.
Highlights
The role of neutrophils in solid tumor metastasis remains largely controversial
To determine whether the immune system integrity affects the role of neutrophils in metastatic colonization, we employed the same experimental metastasis model in immunodeficient host strains including NOD-scid mice, which lack T and B cells, and NOD-scid IL2rγnull (NSG) mice, which lack T, B and natural killer (NK) cells
Using mice with different levels of immune system integrity, our in vivo data suggested that G-CSF-expanded neutrophils were anti-metastatic in NK cell-deficient mice, but pro-metastatic in NK cell-competent mice
Summary
The role of neutrophils in solid tumor metastasis remains largely controversial. In preclinical models of solid tumors, both pro-metastatic and anti-metastatic effects of neutrophils have been reported. In NK cell-deficient mice, granulocyte colony-stimulating factor-expanded neutrophils show an inhibitory effect on the metastatic colonization of breast tumor cells in the lung. Neutrophils function to repress the resident anti-tumor immunity causing an immunosuppressive microenvironment favoring the colonization and outgrowth of the disseminated tumor cells (DTCs)[6,13]. In addition to this immunosuppressive capacity, neutrophils have been shown to facilitate the DTC extravasation, secrete tumor-trophic factors and awaken the dormant DTCs via formation of neutrophil extracellular traps (NETs)[4,13,14]. In the lung metastatic niche, lung-infiltrating neutrophils have been shown to restrain the anti-tumor CD8+ T cell response by producing iNOS6, and were capable of suppressing intraluminal natural killer (NK) cells, the underlying mechanisms were not fully characterized[13]
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