IL-17-producing γδ T cells and neutrophils conspire to promote breast cancer metastasis

Coffelt, S. B. et al. (2015) IL-17-producing γδ T cells and neutrophils conspire to promote breast cancer metastasis. Nature, 522(7556), pp. 345-348. (doi:10.1038/nature14282) (PMID:25822788) (PMCID:PMC4475637)

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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 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.

Item Type:Articles (Letter)
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Coffelt, Dr Seth
Authors: Coffelt, S. B., Kersten, K., Doornebal, C. W., Weiden, J., Vrijland, K., Hau, C.-S., Verstegen, N. J.M., Ciampricotti, M., Hawinkels, L. J.A.C., Jonkers, J., and de Visser, K. E.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Nature
Publisher:Nature Publishing Group
ISSN:0028-0836
ISSN (Online):1476-4687
Published Online:30 March 2015
Copyright Holders:Copyright © 2015 MacMillan Publishers
First Published:First published in Nature 522(7556:345-348
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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