* p<0.05, ** p<0.01, *** p<0.001 as determined by Mann-Whitney U test or Kruskal-Wallis test followed by Dunn’s post test.Ī, Schematic illustration of the neutrophil depletion experiment in the spontaneous metastasis model. g, Kinetics of neutrophil proportions in blood (gated on CD45 + cells), before and after surgical removal of their primary tumor (n = 5). Recipient mice transplanted with KEP tumor pieces were sacrificed at the tumor size shown (n = 6, 5, 6, and 7 mice for 0, 9, 25, 100 mm 2 respectively). f, Kinetics of neutrophil accumulation in various organs of the metastasis model by flow cytometry after gating on CD45 + cells. Scale bar = 100 μm (n = 3, 5, 6, 6 and 3 mice for 0, 9, 25, 100 mm 2 and metastasis respectively). For quantification in lungs with metastases, neutrophils residing inside metastases were excluded. Data were generated from mock-transplanted, non-tumor-bearing mice (0 mm 2), or tumor-transplanted recipient mice sacrificed when tumors reached the tumor size shown or when mice exhibited signs of respiratory distress due to pulmonary metastasis. e, Representative images of Ly6G-stained lung sections and quantification of neutrophil accumulation in the metastasis model. Neutrophils were not detectable in WT mammary glands (n = 5 WT, 7 KEP mice). d, Quantification of neutrophil accumulation in various organs determined by flow cytometry and gated on CD45 + cells. c, Absolute neutrophil counts in blood of WT and tumor-bearing KEP mice (n = 4 WT, 8 KEP). b, Quantification of neutrophil accumulation per field of view (FOV) in various organs by immunohistochemistry using the 7/4 antibody (n = 6 WT, 9 KEP mice). Our data indicate that targeting this novel cancer-cell-initiated domino effect within the immune system-the γδ T cell/IL-17/neutrophil axis-represents a new strategy to inhibit metastatic disease.Ī, Representative images of neutrophils identified by the 7/4 antibody in lung sections in wild-type (WT) or KEP mice. Moreover, the absence of γδ T cells or neutrophils profoundly reduces pulmonary and lymph node metastases without influencing primary tumour progression. Neutralization of IL-17 or G-CSF and absence of γδ T cells prevents neutrophil accumulation and downregulates the T-cell-suppressive phenotype of neutrophils. Tumour-induced neutrophils acquire the ability to suppress cytotoxic T lymphocytes carrying the CD8 antigen, which limit the establishment of metastases. We mechanistically demonstrate that interleukin (IL)-1β elicits IL-17 expression from gamma delta (γδ) T cells, resulting in systemic, granulocyte colony-stimulating factor (G-CSF)-dependent expansion and polarization of neutrophils in mice bearing mammary tumours. Here we show that tumours maximize their chance of metastasizing by evoking a systemic inflammatory cascade in mouse models of spontaneous breast cancer metastasis. However, the precise contribution of tumour-induced systemic inflammation to metastasis and the mechanisms regulating systemic inflammation are poorly understood. Within this local microenvironment and in distant organs, immune cells and their mediators are known to facilitate metastasis formation. The different steps of the metastatic cascade rely on reciprocal interactions between cancer cells and their microenvironment. Metastatic disease remains the primary cause of death for patients with breast cancer.
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