Letter | Published:

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

Nature volume 522, pages 345348 (18 June 2015) | Download Citation

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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.

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Change history

  • 17 June 2015

    The mouse model name in Fig. 1a was corrected.

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Gene Expression Omnibus

Data deposits

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. (k.d.visser@nki.nl).

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Acknowledgements

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.

Author information

Author notes

    • Kelly Kersten
    •  & Chris W. Doornebal

    *These authors contributed equally to this work.

Affiliations

  1. Division of Immunology, Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, The Netherlands

    • Seth B. Coffelt
    • , Kelly Kersten
    • , Chris W. Doornebal
    • , Jorieke Weiden
    • , Kim Vrijland
    • , Cheei-Sing Hau
    • , Niels J. M. Verstegen
    • , Metamia Ciampricotti
    •  & Karin E. de Visser
  2. Department of Molecular Cell Biology, Leiden University Medical Center, Albinusdreef 2, Leiden, 2300 RC, The Netherlands

    • Lukas J. A. C. Hawinkels
  3. Centre for Biomedical Genetics, Leiden University Medical Center, Albinusdreef 2, Leiden, 2300 RC, The Netherlands

    • Lukas J. A. C. Hawinkels
  4. Division of Molecular Pathology, Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, The Netherlands

    • Jos Jonkers

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Contributions

S.B.C., J.J. and K.E.dV. conceived the ideas and designed the experiments. S.B.C., C.W.D., K.K., J.W., C.H., K.V., N.J.V., M.C., L.J.A.C.H. and K.E.dV. performed the experiments. S.B.C., C.W.D., K.K., J.W., C.H., K.V., N.J.V., L.J.A.C.H. and K.E.dV. analysed the data. S.B.C., K.K. and K.E.dV. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Karin E. de Visser.

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DOI

https://doi.org/10.1038/nature14282

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