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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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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).


  1. 1.

    & Microenvironmental regulation of tumor progression and metastasis. Nature Med. 19, 1423–1437 (2013)

  2. 2.

    & The tumour-induced systemic environment as a critical regulator of cancer progression and metastasis. Nature Cell Biol. 16, 717–727 (2014)

  3. 3.

    , & Usefulness of pretreatment neutrophil to lymphocyte ratio in predicting disease-specific survival in breast cancer patients. J. Breast Cancer 16, 55–59 (2013)

  4. 4.

    et al. Usefulness of the neutrophil-to-lymphocyte ratio in predicting short- and long-term mortality in breast cancer patients. Ann. Surg. Oncol. 19, 217–224 (2012)

  5. 5.

    et al. Tumor entrained neutrophils inhibit seeding in the premetastatic lung. Cancer Cell 20, 300–314 (2011)

  6. 6.

    et al. Granulocyte-colony stimulating factor promotes lung metastasis through mobilization of Ly6G+Ly6C+ granulocytes. Proc. Natl Acad. Sci. USA 107, 21248–21255 (2010)

  7. 7.

    et al. Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma. Nature 507, 109–113 (2014)

  8. 8.

    et al. Somatic inactivation of E-cadherin and p53 in mice leads to metastatic lobular mammary carcinoma through induction of anoikis resistance and angiogenesis. Cancer Cell 10, 437–449 (2006)

  9. 9.

    et al. A preclinical mouse model of invasive lobular breast cancer metastasis. Cancer Res. 73, 353–363 (2013)

  10. 10.

    et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820–827 (2005)

  11. 11.

    et al. Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell 15, 35–44 (2009)

  12. 12.

    et al. Inhibition of the Kit ligand/c-Kit axis attenuates metastasis in a mouse model mimicking local breast cancer relapse after radiotherapy. Clin. Cancer Res. 18, 4365–4374 (2012)

  13. 13.

    et al. MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. Cancer Cell 2, 289–300 (2002)

  14. 14.

    , , & Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis. Nature Cell Biol. 8, 1369–1375 (2006)

  15. 15.

    , , & Immune suppression by neutrophils and granulocytic myeloid-derived suppressor cells: similarities and differences. Cell. Mol. Life Sci. 70, 3813–3827 (2013)

  16. 16.

    et al. Myeloid suppressor lines inhibit T cell responses by an NO-dependent mechanism. J. Immunol. 168, 689–695 (2002)

  17. 17.

    , , , & Suppression of T cell proliferation by tumor-induced granulocyte-macrophage progenitor cells producing transforming growth factor-β and nitric oxide. J. Immunol. 156, 1916–1922 (1996)

  18. 18.

    et al. Nitric oxide involvement in tumor-induced immunosuppression. J. Immunol. 152, 5077–5083 (1994)

  19. 19.

    & Colony stimulating factors and myeloid cell biology in health and disease. Trends Immunol. 34, 81–89 (2013)

  20. 20.

    et al. Critical regulation of early Th17 cell differentiation by interleukin-1 signaling. Immunity 30, 576–587 (2009)

  21. 21.

    et al. Pivotal role of dermal IL-17-producing γδ T cells in skin inflammation. Immunity 35, 596–610 (2011)

  22. 22.

    et al. Cxcr2 and Cxcl5 regulate the IL-17/G-CSF axis and neutrophil homeostasis in mice. J. Clin. Invest. 122, 974–986 (2012)

  23. 23.

    et al. Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity. Immunity 31, 331–341 (2009)

  24. 24.

    et al. Requirement of endogenous stem cell factor and granulocyte-colony-stimulating factor for IL-17-mediated granulopoiesis. J. Immunol. 164, 4783–4789 (2000)

  25. 25.

    et al. Polarization of tumor-associated neutrophil phenotype by TGF-β: “N1” versus “N2” TAN. Cancer Cell 16, 183–194 (2009)

  26. 26.

    et al. Prognostic value of chemotherapy-induced neutropenia in early-stage breast cancer. Breast Cancer Res. Treat. 131, 483–490 (2012)

  27. 27.

    et al. Tumor-infiltrating γδ T lymphocytes predict clinical outcome in human breast cancer. J. Immunol. 189, 5029–5036 (2012)

  28. 28.

    et al. TGF-β receptor II loss promotes mammary carcinoma progression by Th17 dependent mechanisms. Cancer Discov 1, 430–441 (2011)

  29. 29.

    et al. Interleukin-17-producing cell infiltration in the breast cancer tumour microenvironment is a poor prognostic factor. Histopathology 63, 225–233 (2013)

  30. 30.

    et al. Chitinase-like proteins promote IL-17-mediated neutrophilia in a tradeoff between nematode killing and host damage. Nature Immunol. 15, 1116–1125 (2014)

  31. 31.

    , & De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. Cancer Cell 7, 411–423 (2005)

  32. 32.

    , , , & Chemotherapy response of spontaneous mammary tumors is independent of the adaptive immune system. Nature Med. 18, 344–346 (2012)

  33. 33.

    et al. Regulation of cutaneous malignancy by γδ T cells. Science 294, 605–609 (2001)

  34. 34.

    et al. Development of metastatic HER2+ breast cancer is independent of the adaptive immune system. J. Pathol. 224, 56–66 (2011)

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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.


  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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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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