title: IL-17-producing γδ T cells and neutrophils conspire to promote breast cancer metastasis.
abstract: 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 formation. 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.
authors.affiliation: Divisions of Immunology, Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, The Netherlands.
authors.forename: Seth B
authors.initials: SB
authors.lastname: Coffelt
authors.affiliation: Divisions of Immunology, Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, The Netherlands.
authors.forename: Kelly
authors.initials: K
authors.lastname: Kersten
authors.affiliation: Divisions of Immunology, Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, The Netherlands.
authors.forename: Chris W
authors.initials: CW
authors.lastname: Doornebal
authors.affiliation: Divisions of Immunology, Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, The Netherlands.
authors.forename: Jorieke
authors.initials: J
authors.lastname: Weiden
authors.affiliation: Divisions of Immunology, Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, The Netherlands.
authors.forename: Kim
authors.initials: K
authors.lastname: Vrijland
authors.affiliation: Divisions of Immunology, Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, The Netherlands.
authors.forename: Cheei-Sing
authors.initials: CS
authors.lastname: Hau
authors.affiliation: Divisions of Immunology, Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, The Netherlands.
authors.forename: Niels J M
authors.initials: NJM
authors.lastname: Verstegen
authors.affiliation: Divisions of Immunology, Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, The Netherlands.
authors.forename: Metamia
authors.initials: M
authors.lastname: Ciampricotti
authors.affiliation: Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center, Leiden, 2300 RC, The Netherlands.
authors.forename: Lukas J A C
authors.initials: LJAC
authors.lastname: Hawinkels
authors.affiliation: Molecular Pathology, Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, The Netherlands.
authors.forename: Jos
authors.initials: J
authors.lastname: Jonkers
authors.affiliation: Divisions of Immunology, Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, The Netherlands.
authors.forename: Karin E
authors.initials: KE
authors.lastname: de Visser
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000276:immunology; D053583:Interleukin-1beta / Q000276:immunology; D008168:Lung / Q000473:pathology; D008175:Lung Neoplasms / Q000276:immunology / Q000473:pathology / Q000556:secondary; D008207:Lymphatic Metastasis / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D009362:Neoplasm Metastasis / Q000276:immunology* / Q000473:pathology*; D009504:Neutrophils / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D010641:Phenotype; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism*; D059016:Tumor Microenvironment
chemical_list: D020381:Interleukin-17; D053583:Interleukin-1beta; D016179:Granulocyte Colony-Stimulating Factor
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