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Unique pattern of neutrophil migration and function during tumor progression

Abstract

Although neutrophils have been linked to the formation of the pre-metastatic niche, the mechanism of their migration to distant, uninvolved tissues has remained elusive. We report that bone marrow neutrophils from mice with early-stage cancer exhibited much more spontaneous migration than that of control neutrophils from tumor-free mice. These cells lacked immunosuppressive activity but had elevated rates of oxidative phosphorylation and glycolysis, and increased production of ATP, relative to that of control neutrophils. Their enhanced spontaneous migration was mediated by autocrine ATP signaling through purinergic receptors. In ectopic tumor models and late stages of cancer, bone marrow neutrophils demonstrated potent immunosuppressive activity. However, these cells had metabolic and migratory activity indistinguishable from that of control neutrophils. A similar pattern of migration was observed for neutrophils and polymorphonuclear myeloid-derived suppressor cells from patients with cancer. These results elucidate the dynamic changes that neutrophils undergo in cancer and demonstrate the mechanism of neutrophils’ contribution to early tumor dissemination.

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Fig. 1: Neutrophils from the BM of three mouse GEMs exhibit increased spontaneous migration.
Fig. 2: Neutrophils from mouse GEMs exhibit increased spontaneous migration, but those from transplantable tumor mouse models do not.
Fig. 3: Neutrophils from the early stages of an orthotopic lung cancer model exhibit increased spontaneous migration, but those from late stages do not.
Fig. 4: Transcriptome and functional activity of neutrophils in TB mice.
Fig. 5: Suppressive activity of BM neutrophils in TB mice.
Fig. 6: PM-LCs have increased metabolic flux through oxidative phosphorylation and glycolysis and have more ATP than that of control neutrophils.
Fig. 7: The spontaneous migration of PM-LCs is dependent on pannexin-1 hemichannels, extracellular ATP and P2X and P2Y receptors.
Fig. 8: Neutrophil migration in patients with cancer.

Data availability

The data that support the findings of this study are available from the corresponding author upon request. Source data are available for Figs. 18. RNAseq data were deposited in the GEO data repository under accession code GSE118366.

References

  1. 1.

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

    CAS  Article  Google Scholar 

  2. 2.

    Eruslanov, E. B. et al. Tumor-associated neutrophils stimulate T cell responses in early-stage human lung cancer. J. Clin. Invest. 124, 5466–5480 (2014).

    Article  Google Scholar 

  3. 3.

    Veglia, F., Perego, M. & Gabrilovich, D. Myeloid-derived suppressor cells coming of age. Nat. Immunol. 19, 108–119 (2018).

    CAS  Article  Google Scholar 

  4. 4.

    Coffelt, S. B., Wellenstein, M. D. & de Visser, K. E. Neutrophils in cancer: neutral no more. Nat. Rev. Cancer 16, 431–446 (2016).

    CAS  Article  Google Scholar 

  5. 5.

    Zhou, J., Nefedova, Y., Lei, A. & Gabrilovich, D. Neutrophils and PMN-MDSC: Their biological role and interaction with stromal cells. Semin. Immunol. 35, 19–28 (2018).

    CAS  Article  Google Scholar 

  6. 6.

    Ortiz, M. L. et al. Immature myeloid cells directly contribute to skin tumor development by recruiting IL-17-producing CD4+ T cells. J. Exp. Med. 212, 351–367 (2015).

    CAS  Article  Google Scholar 

  7. 7.

    Ortiz, M. L., Lu, L., Ramachandran, I. & Gabrilovich, D. I. Myeloid-derived suppressor cells in the development of lung cancer. Cancer Immunol. Res. 2, 50–58 (2014).

    CAS  Article  Google Scholar 

  8. 8.

    Bronte, V. et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat. Commun. 7, 12150 (2016).

    CAS  Article  Google Scholar 

  9. 9.

    Seyfried, T. N. & Huysentruyt, L. C. On the origin of cancer metastasis. Crit. Rev. Oncog. 18, 43–73 (2013).

    Article  Google Scholar 

  10. 10.

    Achberger, S. et al. Circulating immune cell and microRNA in patients with uveal melanoma developing metastatic disease. Mol. Immunol. 58, 182–186 (2014).

    CAS  Article  Google Scholar 

  11. 11.

    Weide, B. et al. Myeloid-derived suppressor cells predict survival of patients with advanced melanoma: comparison with regulatory T cells and NY-ESO-1- or melan-A-specific T cells. Clin. Cancer Res. 20, 1601–1609 (2014).

    CAS  Article  Google Scholar 

  12. 12.

    Condamine, T., Ramachandran, I., Youn, J. I. & Gabrilovich, D. I. Regulation of tumor metastasis by myeloid-derived suppressor cells. Annu. Rev. Med. 66, 97–110 (2015).

    CAS  Article  Google Scholar 

  13. 13.

    Coffelt, S. B. et al. IL-17-producing γδ T cells and neutrophils conspire to promote breast cancer metastasis. Nature 522, 345–348 (2015).

    CAS  Article  Google Scholar 

  14. 14.

    Toh, B. et al. Mesenchymal transition and dissemination of cancer cells is driven by myeloid-derived suppressor cells infiltrating the primary tumor. PLoS Biol. 9, e1001162 (2011).

    CAS  Article  Google Scholar 

  15. 15.

    Liu, Y. et al. MicroRNA-494 is required for the accumulation and functions of tumor-expanded myeloid-derived suppressor cells via targeting of PTEN. J. Immunol. 188, 5500–5510 (2012).

    CAS  Article  Google Scholar 

  16. 16.

    Yang, L. et al. Abrogation of TGF β signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. Cancer Cell 13, 23–35 (2008).

    CAS  Article  Google Scholar 

  17. 17.

    Huh, S. J., Liang, S., Sharma, A., Dong, C. & Robertson, G. P. Transiently entrapped circulating tumor cells interact with neutrophils to facilitate lung metastasis development. Cancer Res. 70, 6071–6082 (2010).

    CAS  Article  Google Scholar 

  18. 18.

    Ichikawa, M., Williams, R., Wang, L., Vogl, T. & Srikrishna, G. S100A8/A9 activate key genes and pathways in colon tumor progression. Mol. Cancer Res. 9, 133–148 (2011).

    CAS  Article  Google Scholar 

  19. 19.

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

    CAS  Article  Google Scholar 

  20. 20.

    Kolaczkowska, E. & Kubes, P. Neutrophil recruitment and function in health and inflammation. Nat. Rev. Immunol. 13, 159–175 (2013).

    CAS  Article  Google Scholar 

  21. 21.

    Mócsai, A., Walzog, B. & Lowell, C. A. Intracellular signalling during neutrophil recruitment. Cardiovasc. Res. 107, 373–385 (2015).

    Article  Google Scholar 

  22. 22.

    Kumar, V., Patel, S., Tcyganov, E. & Gabrilovich, D. I. The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol. 37, 208–220 (2016).

    CAS  Article  Google Scholar 

  23. 23.

    Brandau, S. et al. Myeloid-derived suppressor cells in the peripheral blood of cancer patients contain a subset of immature neutrophils with impaired migratory properties. J. Leukoc. Biol. 89, 311–317 (2011).

    CAS  Article  Google Scholar 

  24. 24.

    Kato, M. et al. Transgenic mouse model for skin malignant melanoma. Oncogene 17, 1885–1888 (1998).

    CAS  Article  Google Scholar 

  25. 25.

    Hingorani, S. R. et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7, 469–483 (2005).

    CAS  Article  Google Scholar 

  26. 26.

    Greenberg, N. M. et al. Prostate cancer in a transgenic mouse. Proc. Natl. Acad. Sci. USA 92, 3439–3443 (1995).

    CAS  Article  Google Scholar 

  27. 27.

    Evans, R.A. et al. Lack of immunoediting in murine pancreatic cancer reversed with neoantigen. JCI Insight 1, e88328 (2016).

  28. 28.

    Casbon, A. J. et al. Invasive breast cancer reprograms early myeloid differentiation in the bone marrow to generate immunosuppressive neutrophils. Proc. Natl. Acad. Sci. USA 112, E566–E575 (2015).

    CAS  Article  Google Scholar 

  29. 29.

    Biswas, S. K. Metabolic Reprogramming of immune cells in cancer progression. Immunity 43, 435–449 (2015).

    CAS  Article  Google Scholar 

  30. 30.

    Chen, Y. et al. ATP release guides neutrophil chemotaxis via P2Y2 and A3 receptors. Science 314, 1792–1795 (2006).

    CAS  Article  Google Scholar 

  31. 31.

    Chen, Y. et al. Purinergic signaling: a fundamental mechanism in neutrophil activation. Sci. Signal. 3, ra45 (2010).

    PubMed  PubMed Central  Google Scholar 

  32. 32.

    Junger, W. G. Purinergic regulation of neutrophil chemotaxis. Cell. Mol. Life Sci. 65, 2528–2540 (2008).

    CAS  Article  Google Scholar 

  33. 33.

    Junger, W. G. Immune cell regulation by autocrine purinergic signalling. Nat. Rev. Immunol. 11, 201–212 (2011).

    CAS  Article  Google Scholar 

  34. 34.

    Lecut, C. et al. P2X1 ion channels promote neutrophil chemotaxis through Rho kinase activation. J. Immunol. 183, 2801–2809 (2009).

    CAS  Article  Google Scholar 

  35. 35.

    Hind, L. E., Vincent, W. J. & Huttenlocher, A. Leading from the back: the role of the uropod in neutrophil polarization and migration. Dev. Cell 38, 161–169 (2016).

    CAS  Article  Google Scholar 

  36. 36.

    Yang, H. W., Collins, S. R. & Meyer, T. Locally excitable Cdc42 signals steer cells during chemotaxis. Nat. Cell Biol. 18, 191–201 (2016).

    CAS  Article  Google Scholar 

  37. 37.

    Condamine, T. et al. Lectin-type oxidized LDL receptor-1 distinguishes population of human polymorphonuclear myeloid-derived suppressor cells in cancer patients. Sci. Immunol. 1, aaf8943 (2016).

    Article  Google Scholar 

  38. 38.

    Condamine, T. et al. ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R-mediated apoptosis. J. Clin. Invest. 124, 2626–2639 (2014).

    CAS  Article  Google Scholar 

  39. 39.

    Tybulewicz, V. L. & Henderson, R. B. Rho family GTPases and their regulators in lymphocytes. Nat. Rev. Immunol. 9, 630–644 (2009).

    CAS  Article  Google Scholar 

  40. 40.

    Hammami, I. et al. Immunosuppressive activity enhances central carbon metabolism and bioenergetics in myeloid-derived suppressor cells in vitro models. BMC Cell Biol. 13, 18 (2012).

    CAS  Article  Google Scholar 

  41. 41.

    Hossain, F. et al. Inhibition of fatty acid oxidation modulates immunosuppressive functions of myeloid-derived suppressor cells and enhances cancer therapies. Cancer Immunol. Res. 3, 1236–1247 (2015).

    CAS  Article  Google Scholar 

  42. 42.

    Schug, Z. T. et al. Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress. Cancer Cell 27, 57–71 (2015).

    CAS  Article  Google Scholar 

  43. 43.

    Li, B. & Dewey, C. N. RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinformatics 12, 323 (2011).

    CAS  Article  Google Scholar 

  44. 44.

    Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).

    Article  Google Scholar 

  45. 45.

    Othmer, H. G., Dunbar, S. R. & Alt, W. Models of dispersal in biological systems. J. Math. Biol. 26, 263–298 (1988).

    CAS  Article  Google Scholar 

  46. 46.

    Dunn, G. A. Characterising a kinesis response: time averaged measures of cell speed and directional persistence. Agents Actions Suppl. 12, 14–33 (1983).

    CAS  Google Scholar 

  47. 47.

    Farrell, B. E., Daniele, R. P. & Lauffenburger, D. A. Quantitative relationships between single-cell and cell-population model parameters for chemosensory migration responses of alveolar macrophages to C5a. Cell Motil. Cytoskeleton 16, 279–293 (1990).

    CAS  Article  Google Scholar 

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Acknowledgements

We thank R. Ramakrishnan (H. Lee Moffitt Cancer Center) for the luciferase expressing LL2 tumor cell line; and D. Laxminarasimha for help in animal experiments. This work was supported by the Wistar Institute Animal and Bioinformatics core facilities and by the US National Institutes of Health (P01 CA140043 and T32 CA09171). S.Y. was supported by International Program for Ph.D Candidates, Sun Yat-Sen University, China.

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Investigation, S.P., S.F., J.M., G.D., A.P., C.L., K.A.-T. and M.S.; formal analysis, A.K. and Z.S.; resources, Y.N., L.R.L., C.C., R.H.V., C.M., B.N., N.H., G.M. and M.G.; writing (original draft), S.P. and G.D.; writing (review and editing), J.Z., D.C.A. and D.I.G.; funding acquisition, D.C.A. and D.I.G.; conceptualization and supervision, D.I.G.

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Correspondence to Dmitry I. Gabrilovich.

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Supplementary Figures 1–8 and Supplementary Tables 1 and 2

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Supplementary Video 1

Time lapse video demonstrating spontaneous movement of neutrophils from naïve and RET TB mice. Scale bar = 50 µm

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Patel, S., Fu, S., Mastio, J. et al. Unique pattern of neutrophil migration and function during tumor progression. Nat Immunol 19, 1236–1247 (2018). https://doi.org/10.1038/s41590-018-0229-5

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