Metastatic disease remains the primary cause of death for patients with breast cancer. The different steps of the metastatic cascade rely on reciprocal interactions between cancer cells and their microenvironment. Within this local microenvironment and in distant organs, immune cells and their mediators are known to facilitate metastasis formation1,2. However, the precise contribution of tumour-induced systemic inflammation to metastasis and the mechanisms regulating systemic inflammation are poorly understood. Here we show that tumours maximize their chance of metastasizing by evoking a systemic inflammatory cascade in mouse models of spontaneous breast cancer metastasis. 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. Tumour-induced neutrophils acquire the ability to suppress cytotoxic T lymphocytes carrying the CD8 antigen, which limit the establishment of metastases. 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. Moreover, the absence of γδ T cells or neutrophils profoundly reduces pulmonary and lymph node metastases without influencing primary tumour progression. 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.
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Gene Expression Omnibus
RNA-seq data have been deposited in the Gene Expression Omnibus (GEO) under accession number GSE55633. Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests. Readers are welcome to comment on the online version of the paper. Correspondence and requests for materials should be addressed to K.E.dV. (email@example.com).
This work was supported by a Marie Curie Intra-European Fellowship to S.B.C. (BMDCMET 275610); a European Research Council Consolidator award (INFLAMET 615300) to K.E.dV; grants from the Dutch Cancer Society to K.E.dV and J.J. (2011-5004); Worldwide Cancer Research (AICR 11-0677) to K.E.dV; the Netherlands Organization for Scientific Research NWO VIDI (917.96.307) to K.E.dV; and a Dutch Cancer Society/Bas Mulder Award to L.J.A.C.H. (UL2011-5051). We thank J. Borst, T. Schumacher and J. Coquet for discussions. We thank the core facilities at the Netherlands Cancer Institute. We thank L. Coussens for Rag1−/− mice and A. Hayday for Tcrd−/− mice. We thank C. Ries and K. Wartha for technical assistance.
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Journal of Leukocyte Biology (2019)