Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Neutrophils in cancer: neutral no more

Key Points

  • In patients with solid cancers, neutrophils expand both in the tumour microenvironment and systemically, and are generally associated with poor prognosis.

  • Genetically engineered mouse models for cancer have been crucial in identifying underlying mechanisms by which neutrophils influence tumour initiation, growth and metastasis.

  • Neutrophils exert multifaceted and sometimes opposing roles during cancer initiation, growth and dissemination.

  • Primary tumours activate granulopoiesis in the bone marrow and actively stimulate the release and recruitment of both mature neutrophils and their progenitors.

  • Depending on the spectrum and quantity of soluble mediators produced by cancer cells and cancer-associated cells, neutrophils can be polarized into different activation states by which they elicit various pro- or antitumour functions.

  • Interactions between neutrophils and other (immune) cells are key in exerting their function, and the interaction networks observed in cancer are often highly reminiscent of those seen in other immunological diseases.

  • Neutrophils modulate the efficacy of cancer therapies, and can also serve as biomarkers for progression and therapy response in cancer patients.

  • Now that there is a growing understanding of the impact of neutrophils on cancer, the mechanisms by which neutrophils promote cancer progression may be used as targets to maximize the efficacy of anticancer therapeutics.

Abstract

Neutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. In the cancer setting, a newfound appreciation for neutrophils has come into view. The traditionally held belief that neutrophils are inert bystanders is being challenged by the recent literature. Emerging evidence indicates that tumours manipulate neutrophils, sometimes early in their differentiation process, to create diverse phenotypic and functional polarization states able to alter tumour behaviour. In this Review, we discuss the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Granulopoiesis during homeostasis.
Figure 2: Tumour-induced emergency granulopoiesis.
Figure 3: Neutrophil function in tumour initiation and growth.
Figure 4: Impact of neutrophils on the metastatic cascade.

Similar content being viewed by others

References

  1. Ehrlich, P. Methodologische beitrage zur physiologie und pathologie der verschiedenen formen der leukocyten. Zeitschr. Klin. Med. 1, 553–558 (1880).

    Google Scholar 

  2. Dancey, J. T., Deubelbeiss, K. A., Harker, L. A. & Finch, C. A. Neutrophil kinetics in man. J. Clin. Invest. 58, 705–715 (1976).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Templeton, A. J. et al. Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis. J. Natl Cancer Inst. 106, dju124 (2014). This comprehensive study demonstrated the strong prognostic and predictive value of NLRs in human cancers.

    Article  CAS  PubMed  Google Scholar 

  4. Gentles, A. J. et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat. Med. 21, 938–945 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Borregaard, N. Neutrophils, from marrow to microbes. Immunity 33, 657–670 (2010).

    Article  CAS  PubMed  Google Scholar 

  6. Görgens, A. et al. Revision of the human hematopoietic tree: granulocyte subtypes derive from distinct hematopoietic lineages. Cell Rep. 3, 1539–1552 (2013).

    Article  CAS  PubMed  Google Scholar 

  7. Friedman, A. D. Transcriptional control of granulocyte and monocyte development. Oncogene 26, 6816–6828 (2007).

    Article  CAS  PubMed  Google Scholar 

  8. Fiedler, K. & Brunner, C. The role of transcription factors in the guidance of granulopoiesis. Am. J. Blood Res. 2, 57–65 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Rosenbauer, F. & Tenen, D. G. Transcription factors in myeloid development: balancing differentiation with transformation. Nat. Rev. Immunol. 7, 105–117 (2007).

    Article  CAS  PubMed  Google Scholar 

  10. Pillay, J., Tak, T., Kamp, V. M. & Koenderman, L. Immune suppression by neutrophils and granulocytic myeloid-derived suppressor cells: similarities and differences. Cell. Mol. Life Sci. 70, 3813–3827 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Manz, M. G. & Boettcher, S. Emergency granulopoiesis. Nat. Rev. Immunol. 14, 302–314 (2014).

    Article  CAS  PubMed  Google Scholar 

  12. Hager, M., Cowland, J. B. & Borregaard, N. Neutrophil granules in health and disease. J. Intern. Med. 268, 25–34 (2010).

    CAS  PubMed  Google Scholar 

  13. Borregaard, N., Sorensen, O. E. & Theilgaard-Monch, K. Neutrophil granules: a library of innate immunity proteins. Trends Immunol. 28, 340–345 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. Cortez-Retamozo, V. et al. Origins of tumor-associated macrophages and neutrophils. Proc. Natl Acad. Sci. USA 109, 2491–2496 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Lieschke, G. J. et al. Mice lacking granulocyte colony-stimulating factor have chronic neutropenia, granulocyte and macrophage progenitor cell deficiency, and impaired neutrophil mobilization. Blood 84, 1737–1746 (1994).

    CAS  PubMed  Google Scholar 

  16. Liu, F., Wu, H. Y., Wesselschmidt, R., Kornaga, T. & Link, D. C. Impaired production and increased apoptosis of neutrophils in granulocyte colony-stimulating factor receptor-deficient mice. Immunity 5, 491–501 (1996).

    Article  CAS  PubMed  Google Scholar 

  17. Richards, M. K., Liu, F., Iwasaki, H., Akashi, K. & Link, D. C. Pivotal role of granulocyte colony-stimulating factor in the development of progenitors in the common myeloid pathway. Blood 102, 3562–3568 (2003).

    Article  CAS  PubMed  Google Scholar 

  18. McKinstry, W. J. et al. Cytokine receptor expression on hematopoietic stem and progenitor cells. Blood 89, 65–71 (1997).

    CAS  PubMed  Google Scholar 

  19. Adolfsson, J. et al. Identification of Flt3+ lympho-myeloid stem cells lacking erythro-megakaryocytic potential a revised road map for adult blood lineage commitment. Cell 121, 295–306 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Panopoulos, A. D. et al. STAT3 governs distinct pathways in emergency granulopoiesis and mature neutrophils. Blood 108, 3682–3690 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Strauss, L. et al. RORC1 regulates tumor-promoting “emergency” granulo-monocytopoiesis. Cancer Cell 28, 253–269 (2015).

    Article  CAS  PubMed  Google Scholar 

  22. Molineux, G., Migdalska, A., Szmitkowski, M., Zsebo, K. & Dexter, T. M. The effects on hematopoiesis of recombinant stem cell factor (ligand for c-kit) administered in vivo to mice either alone or in combination with granulocyte colony-stimulating factor. Blood 78, 961–966 (1991).

    CAS  PubMed  Google Scholar 

  23. Liu, F., Poursine-Laurent, J., Wu, H. Y. & Link, D. C. Interleukin-6 and the granulocyte colony-stimulating factor receptor are major independent regulators of granulopoiesis in vivo but are not required for lineage commitment or terminal differentiation. Blood 90, 2583–2590 (1997).

    CAS  PubMed  Google Scholar 

  24. Seymour, J. F. et al. Mice lacking both granulocyte colony-stimulating factor (CSF) and granulocyte-macrophage CSF have impaired reproductive capacity, perturbed neonatal granulopoiesis, lung disease, amyloidosis, and reduced long-term survival. Blood 90, 3037–3049 (1997).

    CAS  PubMed  Google Scholar 

  25. 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). This study demonstrated mechanistically how tumours drive myeloid differentiation towards immunosuppressive neutrophils.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Coffelt, S. B. et al. IL-17-producing gammadelta T cells and neutrophils conspire to promote breast cancer metastasis. Nature 522, 345–348 (2015). This mechanistic study revealed that primary tumours induce a systemic inflammatory cascade to promote metastasis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Waight, J. D., Hu, Q., Miller, A., Liu, S. & Abrams, S. I. Tumor-derived G-CSF facilitates neoplastic growth through a granulocytic myeloid-derived suppressor cell-dependent mechanism. PLoS ONE 6, e27690 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 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). This paper showed how tumours directly instruct neutrophils to drive metastasis.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Bayne, L. J. et al. Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer. Cancer Cell 21, 822–835 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Pylayeva-Gupta, Y., Lee, K. E., Hajdu, C. H., Miller, G. & Bar-Sagi, D. Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia. Cancer Cell 21, 836–847 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kuonen, F. 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).

    Article  CAS  PubMed  Google Scholar 

  32. Semerad, C. L., Liu, F., Gregory, A. D., Stumpf, K. & Link, D. C. G-CSF is an essential regulator of neutrophil trafficking from the bone marrow to the blood. Immunity 17, 413–423 (2002).

    Article  CAS  PubMed  Google Scholar 

  33. Ma, Q., Jones, D. & Springer, T. A. The chemokine receptor CXCR4 is required for the retention of B lineage and granulocytic precursors within the bone marrow microenvironment. Immunity 10, 463–471 (1999).

    Article  CAS  PubMed  Google Scholar 

  34. Martin, C. et al. Chemokines acting via CXCR2 and CXCR4 control the release of neutrophils from the bone marrow and their return following senescence. Immunity 19, 583–593 (2003).

    Article  CAS  PubMed  Google Scholar 

  35. Suratt, B. T. et al. Role of the CXCR4/SDF-1 chemokine axis in circulating neutrophil homeostasis. Blood 104, 565–571 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Eash, K. J., Means, J. M., White, D. W. & Link, D. C. CXCR4 is a key regulator of neutrophil release from the bone marrow under basal and stress granulopoiesis conditions. Blood 113, 4711–4719 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Eash, K. J., Greenbaum, A. M., Gopalan, P. K. & Link, D. C. CXCR2 and CXCR4 antagonistically regulate neutrophil trafficking from murine bone marrow. J. Clin. Invest. 120, 2423–2431 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kohler, A. et al. G-CSF-mediated thrombopoietin release triggers neutrophil motility and mobilization from bone marrow via induction of Cxcr2 ligands. Blood 117, 4349–4357 (2011). References 36–38 demonstrated key mechanisms of neutrophil production and release in homeostasis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Levesque, J. P. et al. Characterization of hematopoietic progenitor mobilization in protease-deficient mice. Blood 104, 65–72 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. Burdon, P. C., Martin, C. & Rankin, S. M. The CXC chemokine MIP-2 stimulates neutrophil mobilization from the rat bone marrow in a CD49d-dependent manner. Blood 105, 2543–2548 (2005).

    Article  CAS  PubMed  Google Scholar 

  41. Petty, J. M., Lenox, C. C., Weiss, D. J., Poynter, M. E. & Suratt, B. T. Crosstalk between CXCR4/stromal derived factor-1 and VLA-4/VCAM-1 pathways regulates neutrophil retention in the bone marrow. J. Immunol. 182, 604–612 (2009).

    Article  CAS  PubMed  Google Scholar 

  42. Wengner, A. M., Pitchford, S. C., Furze, R. C. & Rankin, S. M. The coordinated action of G-CSF and ELR + CXC chemokines in neutrophil mobilization during acute inflammation. Blood 111, 42–49 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Petit, I. et al. G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4. Nat. Immunol. 3, 687–694 (2002).

    Article  CAS  PubMed  Google Scholar 

  44. Semerad, C. L. et al. G-CSF potently inhibits osteoblast activity and CXCL12 mRNA expression in the bone marrow. Blood 106, 3020–3027 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kim, H. K., De La Luz Sierra, M., Williams, C. K., Gulino, A. V. & Tosato, G. G-CSF down-regulation of CXCR4 expression identified as a mechanism for mobilization of myeloid cells. Blood 108, 812–820 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Gordy, C., Pua, H., Sempowski, G. D. & He, Y. W. Regulation of steady-state neutrophil homeostasis by macrophages. Blood 117, 618–629 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Tittel, A. P. et al. Functionally relevant neutrophilia in CD11c diphtheria toxin receptor transgenic mice. Nat. Methods 9, 385–390 (2012).

    Article  CAS  PubMed  Google Scholar 

  48. Jiao, J. et al. Central role of conventional dendritic cells in regulation of bone marrow release and survival of neutrophils. J. Immunol. 192, 3374–3382 (2014).

    Article  CAS  PubMed  Google Scholar 

  49. Stark, M. A. et al. Phagocytosis of apoptotic neutrophils regulates granulopoiesis via IL-23 and IL-17. Immunity 22, 285–294 (2005). This study revealed key mechanisms of neutrophil clearance in homeostasis.

    Article  CAS  PubMed  Google Scholar 

  50. Cua, D. J. & Tato, C. M. Innate IL-17-producing cells: the sentinels of the immune system. Nat. Rev. Immunol. 10, 479–489 (2010).

    Article  CAS  PubMed  Google Scholar 

  51. Gaffen, S. L., Jain, R., Garg, A. V. & Cua, D. J. The IL-23–IL-17 immune axis: from mechanisms to therapeutic testing. Nat. Rev. Immunol. 14, 585–600 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  53. Forlow, S. B. et al. Increased granulopoiesis through interleukin-17 and granulocyte colony-stimulating factor in leukocyte adhesion molecule-deficient mice. Blood 98, 3309–3314 (2001).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Deshmukh, H. S. et al. The microbiota regulates neutrophil homeostasis and host resistance to Escherichia coli K1 sepsis in neonatal mice. Nat. Med. 20, 524–530 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Ueda, Y., Cain, D. W., Kuraoka, M., Kondo, M. & Kelsoe, G. IL-1R type I-dependent hemopoietic stem cell proliferation is necessary for inflammatory granulopoiesis and reactive neutrophilia. J. Immunol. 182, 6477–6484 (2009).

    Article  CAS  PubMed  Google Scholar 

  57. Mankan, A. K. et al. TNF-α-dependent loss of IKKbeta-deficient myeloid progenitors triggers a cytokine loop culminating in granulocytosis. Proc. Natl Acad. Sci. USA 108, 6567–6572 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Acharyya, S. et al. A CXCL1 paracrine network links cancer chemoresistance and metastasis. Cell 150, 165–178 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Carmi, Y. et al. Microenvironment-derived IL-1 and IL-17 interact in the control of lung metastasis. J. Immunol. 186, 3462–3471 (2011).

    Article  CAS  PubMed  Google Scholar 

  60. Song, X. et al. CD11b+/Gr-1+ immature myeloid cells mediate suppression of T cells in mice bearing tumors of IL-1β-secreting cells. J. Immunol. 175, 8200–8208 (2005).

    Article  CAS  PubMed  Google Scholar 

  61. Bunt, S. K., Sinha, P., Clements, V. K., Leips, J. & Ostrand-Rosenberg, S. Inflammation induces myeloid-derived suppressor cells that facilitate tumor progression. J. Immunol. 176, 284–290 (2006).

    Article  CAS  PubMed  Google Scholar 

  62. Elkabets, M. et al. IL-1β regulates a novel myeloid-derived suppressor cell subset that impairs NK cell development and function. Eur. J. Immunol. 40, 3347–3357 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Tu, S. et al. Overexpression of interleukin-1β induces gastric inflammation and cancer and mobilizes myeloid-derived suppressor cells in mice. Cancer Cell 14, 408–419 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Sagiv, J. Y. et al. Phenotypic diversity and plasticity in circulating neutrophil subpopulations in cancer. Cell Rep. 10, 562–573 (2015).

    Article  CAS  PubMed  Google Scholar 

  65. Fridlender, Z. G. et al. Polarization of tumor-associated neutrophil phenotype by TGF-β: “N1” versus “N2” TAN. Cancer Cell 16, 183–194 (2009). This report was the first to propose N1/N2 polarization of neutrophils in cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Youn, J. I., Collazo, M., Shalova, I. N., Biswas, S. K. & Gabrilovich, D. I. Characterization of the nature of granulocytic myeloid-derived suppressor cells in tumor-bearing mice. J. Leukoc. Biol. 91, 167–181 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Ueda, Y., Kondo, M. & Kelsoe, G. Inflammation and the reciprocal production of granulocytes and lymphocytes in bone marrow. J. Exp. Med. 201, 1771–1780 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Wu, P. et al. γδT17 cells promote the accumulation and expansion of myeloid-derived suppressor cells in human colorectal cancer. Immunity 40, 785–800 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Denny, M. F. et al. A distinct subset of proinflammatory neutrophils isolated from patients with systemic lupus erythematosus induces vascular damage and synthesizes type I IFNs. J. Immunol. 184, 3284–3297 (2010).

    Article  CAS  PubMed  Google Scholar 

  70. Kim, M. H. et al. Neutrophil survival and c-kit+-progenitor proliferation in Staphylococcus aureus-infected skin wounds promote resolution. Blood 117, 3343–3352 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Pillay, J. et al. A subset of neutrophils in human systemic inflammation inhibits T cell responses through Mac-1. J. Clin. Invest. 122, 327–336 (2012).

    Article  CAS  PubMed  Google Scholar 

  72. Pillay, J. et al. Functional heterogeneity and differential priming of circulating neutrophils in human experimental endotoxemia. J. Leukoc. Biol. 88, 211–220 (2010).

    Article  CAS  PubMed  Google Scholar 

  73. Tsuda, Y. et al. Three different neutrophil subsets exhibited in mice with different susceptibilities to infection by methicillin-resistant Staphylococcus aureus. Immunity 21, 215–226 (2004).

    Article  CAS  PubMed  Google Scholar 

  74. Granick, J. L. et al. Staphylococcus aureus recognition by hematopoietic stem and progenitor cells via TLR2/MyD88/PGE2 stimulates granulopoiesis in wounds. Blood 122, 1770–1778 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Yang, X. D. et al. Histamine deficiency promotes inflammation-associated carcinogenesis through reduced myeloid maturation and accumulation of CD11b+Ly6G+ immature myeloid cells. Nat. Med. 17, 87–95 (2011).

    Article  CAS  PubMed  Google Scholar 

  76. Zhang, D. et al. Neutrophil ageing is regulated by the microbiome. Nature 525, 528–532 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Saverymuttu, S. H., Peters, A. M., Keshavarzian, A., Reavy, H. J. & Lavender, J. P. The kinetics of 111indium distribution following injection of 111indium labelled autologous granulocytes in man. Br. J. Haematol. 61, 675–685 (1985).

    Article  CAS  PubMed  Google Scholar 

  78. Basu, S., Hodgson, G., Katz, M. & Dunn, A. R. Evaluation of role of G-CSF in the production, survival, and release of neutrophils from bone marrow into circulation. Blood 100, 854–861 (2002).

    Article  CAS  PubMed  Google Scholar 

  79. Tak, T., Tesselaar, K., Pillay, J., Borghans, J. A. & Koenderman, L. What's your age again? Determination of human neutrophil half-lives revisited. J. Leukoc. Biol. 94, 595–601 (2013).

    Article  CAS  PubMed  Google Scholar 

  80. Vincent, P. C., Chanana, A. D., Cronkite, E. P. & Joel, D. D. The intravascular survival of neutrophils labeled in vivo. Blood 43, 371–377 (1974).

    CAS  PubMed  Google Scholar 

  81. Cheretakis, C., Leung, R., Sun, C. X., Dror, Y. & Glogauer, M. Timing of neutrophil tissue repopulation predicts restoration of innate immune protection in a murine bone marrow transplantation model. Blood 108, 2821–2826 (2006).

    Article  CAS  PubMed  Google Scholar 

  82. Sawanobori, Y. et al. Chemokine-mediated rapid turnover of myeloid-derived suppressor cells in tumor-bearing mice. Blood 111, 5457–5466 (2008).

    Article  CAS  PubMed  Google Scholar 

  83. Colotta, F., Re, F., Polentarutti, N., Sozzani, S. & Mantovani, A. Modulation of granulocyte survival and programmed cell death by cytokines and bacterial products. Blood 80, 2012–2020 (1992).

    CAS  PubMed  Google Scholar 

  84. Steinbach, K. H. et al. Estimation of kinetic parameters of neutrophilic, eosinophilic, and basophilic granulocytes in human blood. Blut 39, 27–38 (1979).

    Article  CAS  PubMed  Google Scholar 

  85. Li, Z. et al. Gr-1+CD11b+ cells are responsible for tumor promoting effect of TGF-β in breast cancer progression. Int. J. Cancer 131, 2584–2595 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Pang, Y. et al. TGF-β signaling in myeloid cells is required for tumor metastasis. Cancer Discov. 3, 936–951 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Waight, J. D. et al. Myeloid-derived suppressor cell development is regulated by a STAT/IRF-8 axis. J. Clin. Invest. 123, 4464–4478 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Bodogai, M. et al. Immunosuppressive and prometastatic functions of myeloid-derived suppressive cells rely upon education from tumor-associated B cells. Cancer Res. 75, 3456–3465 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Papaspyridonos, M. et al. Id1 suppresses anti-tumour immune responses and promotes tumour progression by impairing myeloid cell maturation. Nat. Commun. 6, 6840 (2015).

    Article  CAS  PubMed  Google Scholar 

  90. Youn, J. I. et al. Epigenetic silencing of retinoblastoma gene regulates pathologic differentiation of myeloid cells in cancer. Nat. Immunol. 14, 211–220 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Jablonska, J., Leschner, S., Westphal, K., Lienenklaus, S. & Weiss, S. Neutrophils responsive to endogenous IFN-β regulate tumor angiogenesis and growth in a mouse tumor model. J. Clin. Invest. 120, 1151–1164 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Wu, C. F. et al. The lack of type I interferon induces neutrophil-mediated pre-metastatic niche formation in the mouse lung. Int. J. Cancer 137, 837–847 (2015).

    Article  CAS  PubMed  Google Scholar 

  93. Mishalian, I. et al. Tumor-associated neutrophils (TAN) develop pro-tumorigenic properties during tumor progression. Cancer Immunol. Immunother. 62, 1745–1756 (2013).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Chen, F. et al. Neutrophils prime a long-lived effector macrophage phenotype that mediates accelerated helminth expulsion. Nat. Immunol. 15, 938–946 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Noy, R. & Pollard, J. W. Tumor-associated macrophages: from mechanisms to therapy. Immunity 41, 49–61 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Qian, B. Z. & Pollard, J. W. Macrophage diversity enhances tumor progression and metastasis. Cell 141, 39–51 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Ruffell, B., Affara, N. I. & Coussens, L. M. Differential macrophage programming in the tumor microenvironment. Trends Immunol. 33, 119–126 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Murray, P. J. et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41, 14–20 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Elinav, E. et al. Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat. Rev. Cancer 13, 759–771 (2013).

    Article  CAS  PubMed  Google Scholar 

  101. Shang, K. et al. Crucial involvement of tumor-associated neutrophils in the regulation of chronic colitis-associated carcinogenesis in mice. PLoS ONE 7, e51848 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Jamieson, T. et al. Inhibition of CXCR2 profoundly suppresses inflammation-driven and spontaneous tumorigenesis. J. Clin. Invest. 122, 3127–3144 (2012). This paper demonstrated the involvement of neutrophils in cancer initiation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Popivanova, B. K. et al. Blocking TNF-α in mice reduces colorectal carcinogenesis associated with chronic colitis. J. Clin. Invest. 118, 560–570 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Katoh, H. et al. CXCR2-expressing myeloid-derived suppressor cells are essential to promote colitis-associated tumorigenesis. Cancer Cell 24, 631–644 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Antonio, N. et al. The wound inflammatory response exacerbates growth of pre-neoplastic cells and progression to cancer. EMBO J. 34, 2219–2236 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Ji, H. et al. K-ras activation generates an inflammatory response in lung tumors. Oncogene 25, 2105–2112 (2006).

    Article  CAS  PubMed  Google Scholar 

  107. Moghaddam, S. J. et al. Promotion of lung carcinogenesis by chronic obstructive pulmonary disease-like airway inflammation in a K-ras-induced mouse model. Am. J. Respir. Cell. Mol. Biol. 40, 443–453 (2009).

    Article  CAS  PubMed  Google Scholar 

  108. Chang, S. H. et al. T helper 17 cells play a critical pathogenic role in lung cancer. Proc. Natl Acad. Sci. USA 111, 5664–5669 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Wislez, M. et al. High expression of ligands for chemokine receptor CXCR2 in alveolar epithelial neoplasia induced by oncogenic kras. Cancer Res. 66, 4198–4207 (2006).

    Article  CAS  PubMed  Google Scholar 

  110. Sparmann, A. & Bar-Sagi, D. Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. Cancer Cell 6, 447–458 (2004).

    Article  CAS  PubMed  Google Scholar 

  111. Gong, L. et al. Promoting effect of neutrophils on lung tumorigenesis is mediated by CXCR2 and neutrophil elastase. Mol. Cancer 12, 154 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  112. Dogan, S. et al. Molecular epidemiology of EGFR and KRAS mutations in 3,026 lung adenocarcinomas: higher susceptibility of women to smoking-related KRAS-mutant cancers. Clin. Cancer Res. 18, 6169–6177 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014).

  114. Takahashi, H., Ogata, H., Nishigaki, R., Broide, D. H. & Karin, M. Tobacco smoke promotes lung tumorigenesis by triggering IKKβ- and JNK1-dependent inflammation. Cancer Cell 17, 89–97 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Houghton, A. M. et al. Neutrophil elastase-mediated degradation of IRS-1 accelerates lung tumor growth. Nat. Med. 16, 219–223 (2010). This study showed how neutrophils directly stimulate cancer cell proliferation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Deryugina, E. I. et al. Tissue-infiltrating neutrophils constitute the major in vivo source of angiogenesis-inducing MMP-9 in the tumor microenvironment. Neoplasia 16, 771–788 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Stoppacciaro, A. et al. Regression of an established tumor genetically modified to release granulocyte colony-stimulating factor requires granulocyte-T cell cooperation and T cell-produced interferon γ. J. Exp. Med. 178, 151–161 (1993).

    Article  CAS  PubMed  Google Scholar 

  118. Pekarek, L. A., Starr, B. A., Toledano, A. Y. & Schreiber, H. Inhibition of tumor growth by elimination of granulocytes. J. Exp. Med. 181, 435–440 (1995).

    Article  CAS  PubMed  Google Scholar 

  119. Seung, L. P., Rowley, D. A., Dubey, P. & Schreiber, H. Synergy between T-cell immunity and inhibition of paracrine stimulation causes tumor rejection. Proc. Natl Acad. Sci. USA 92, 6254–6258 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Nozawa, H., Chiu, C. & Hanahan, D. Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proc. Natl Acad. Sci. USA 103, 12493–12498 (2006). This study demonstrated that neutrophils promote cancer progression by stimulating angiogenesis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Charles, K. A. et al. The tumor-promoting actions of TNF-α involve TNFR1 and IL-17 in ovarian cancer in mice and humans. J. Clin. Invest. 119, 3011–3023 (2009). This study showed a key role for the adaptive immune system in activating neutrophils during tumour progression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Benevides, L. et al. IL17 promotes mammary tumor progression by changing the behavior of tumor cells and eliciting tumorigenic neutrophils recruitment. Cancer Res. 75, 3788–3799 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Bekes, E. M. et al. Tumor-recruited neutrophils and neutrophil TIMP-free MMP-9 regulate coordinately the levels of tumor angiogenesis and efficiency of malignant cell intravasation. Am. J. Pathol. 179, 1455–1470 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Tazzyman, S. et al. Inhibition of neutrophil infiltration into A549 lung tumors in vitro and in vivo using a CXCR2-specific antagonist is associated with reduced tumor growth. Int. J. Cancer 129, 847–858 (2011).

    Article  CAS  PubMed  Google Scholar 

  125. Keane, M. P., Belperio, J. A., Xue, Y. Y., Burdick, M. D. & Strieter, R. M. Depletion of CXCR2 inhibits tumor growth and angiogenesis in a murine model of lung cancer. J. Immunol. 172, 2853–2860 (2004).

    Article  CAS  PubMed  Google Scholar 

  126. Yang, L. et al. Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell 6, 409–421 (2004).

    Article  CAS  PubMed  Google Scholar 

  127. Coussens, L. M., Tinkle, C. L., Hanahan, D. & Werb, Z. MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis. Cell 103, 481–490 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Shojaei, F., Singh, M., Thompson, J. D. & Ferrara, N. Role of Bv8 in neutrophil-dependent angiogenesis in a transgenic model of cancer progression. Proc. Natl Acad. Sci. USA 105, 2640–2645 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Shojaei, F. et al. Bv8 regulates myeloid-cell-dependent tumour angiogenesis. Nature 450, 825–831 (2007). References 128 and 129 showed that neutrophils can promote cancer progression by stimulating angiogenesis.

    Article  CAS  PubMed  Google Scholar 

  130. Gabrilovich, D. I., Ostrand-Rosenberg, S. & Bronte, V. Coordinated regulation of myeloid cells by tumours. Nat. Rev. Immunol. 12, 253–268 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Mantovani, A., Cassatella, M. A., Costantini, C. & Jaillon, S. Neutrophils in the activation and regulation of innate and adaptive immunity. Nat. Rev. Immunol. 11, 519–531 (2011).

    Article  CAS  PubMed  Google Scholar 

  132. Di Mitri, D. et al. Tumour-infiltrating Gr-1+ myeloid cells antagonize senescence in cancer. Nature 515, 134–137 (2014). This paper showed how neutrophils directly affect the cancer cell-intrinsic programme of senescence.

    Article  CAS  PubMed  Google Scholar 

  133. Granot, Z. et al. Tumor entrained neutrophils inhibit seeding in the premetastatic lung. Cancer Cell 20, 300–314 (2011). This paper identified a mechanism by which neutrophils can antagonize metastasis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Finisguerra, V. et al. MET is required for the recruitment of anti-tumoural neutrophils. Nature 522, 349–353 (2015). This study showed that receptor tyrosine kinases are key for neutrophil function in cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Srivastava, M. K. et al. Myeloid suppressor cell depletion augments antitumor activity in lung cancer. PLoS ONE 7, e40677 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Van Egmond, M. & Bakema, J. E. Neutrophils as effector cells for antibody-based immunotherapy of cancer. Semin. Cancer Biol. 23, 190–199 (2013).

    Article  CAS  PubMed  Google Scholar 

  137. De Visser, K. E., Korets, L. V. & Coussens, L. M. De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. Cancer Cell 7, 411–423 (2005).

    Article  CAS  PubMed  Google Scholar 

  138. Andreu, P. et al. FcRγ activation regulates inflammation-associated squamous carcinogenesis. Cancer Cell 17, 121–134 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Wang, G. et al. Targeting YAP-dependent MDSC infiltration impairs tumor progression. Cancer Discov. 6, 80–95 (2016).

    Article  CAS  PubMed  Google Scholar 

  140. Blaisdell, A. et al. Neutrophils oppose uterine epithelial carcinogenesis via debridement of hypoxic tumor cells. Cancer Cell 28, 785–799 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Welch, D. R., Schissel, D. J., Howrey, R. P. & Aeed, P. A. Tumor-elicited polymorphonuclear cells, in contrast to “normal” circulating polymorphonuclear cells, stimulate invasive and metastatic potentials of rat mammary adenocarcinoma cells. Proc. Natl Acad. Sci. USA 86, 5859–5863 (1989). This paper was the first to reveal a metastasis- promoting role for neutrophils.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Ishikawa, M., Koga, Y., Hosokawa, M. & Kobayashi, H. Augmentation of B16 melanoma lung colony formation in C57BL/6 mice having marked granulocytosis. Int. J. Cancer 37, 919–924 (1986).

    Article  CAS  PubMed  Google Scholar 

  143. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Spicer, J. D. et al. Neutrophils promote liver metastasis via Mac-1-mediated interactions with circulating tumor cells. Cancer Res. 72, 3919–3927 (2012).

    Article  CAS  PubMed  Google Scholar 

  145. Tazawa, H. et al. Infiltration of neutrophils is required for acquisition of metastatic phenotype of benign murine fibrosarcoma cells: implication of inflammation-associated carcinogenesis and tumor progression. Am. J. Pathol. 163, 2221–2232 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Cools-Lartigue, J. et al. Neutrophil extracellular traps sequester circulating tumor cells and promote metastasis. J. Clin. Invest. 123, 3446–3458 (2013).

    Article  CAS  PubMed Central  Google Scholar 

  147. Tazzyman, S., Niaz, H. & Murdoch, C. Neutrophil-mediated tumour angiogenesis: subversion of immune responses to promote tumour growth. Semin. Cancer Biol. 23, 149–158 (2013).

    Article  CAS  PubMed  Google Scholar 

  148. Bald, T. et al. Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma. Nature 507, 109–113 (2014). This study demonstrated mechanistically how DNA damage leads to activation of pro-metastatic neutrophils.

    Article  CAS  PubMed  Google Scholar 

  149. Sceneay, J. et al. Primary tumor hypoxia recruits CD11b+/Ly6Cmed/Ly6G+ immune suppressor cells and compromises NK cell cytotoxicity in the premetastatic niche. Cancer Res. 72, 3906–3911 (2012).

    Article  CAS  PubMed  Google Scholar 

  150. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Yan, H. H. et al. Gr-1+CD11b+ myeloid cells tip the balance of immune protection to tumor promotion in the premetastatic lung. Cancer Res. 70, 6139–6149 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Wculek, S. K. & Malanchi, I. Neutrophils support lung colonization of metastasis-initiating breast cancer cells. Nature 528, 413–417 (2015). This paper showed how neutrophil-derived factors affect metastasis-initiating cells to drive cancer spread.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Lämmermann, T. et al. Neutrophil swarms require LTB4 and integrins at sites of cell death in vivo. Nature 498, 371–375 (2013). This paper showed that locally secreted neutrophil-derived factors signal over long distances to regulate neutrophil migration.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  156. Qu, X., Zhuang, G., Yu, L., Meng, G. & Ferrara, N. Induction of Bv8 expression by granulocyte colony-stimulating factor in CD11b+Gr1+ cells: key role of Stat3 signaling. J. Biol. Chem. 287, 19574–19584 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Erler, J. T. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Hirai, H. et al. CCR1-mediated accumulation of myeloid cells in the liver microenvironment promoting mouse colon cancer metastasis. Clin. Exp. Metastasis 31, 977–989 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Kitamura, T. et al. Inactivation of chemokine (C-C motif) receptor 1 (CCR1) suppresses colon cancer liver metastasis by blocking accumulation of immature myeloid cells in a mouse model. Proc. Natl Acad. Sci. USA 107, 13063–13068 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Lopez-Lago, M. A. et al. Neutrophil chemokines secreted by tumor cells mount a lung antimetastatic response during renal cell carcinoma progression. Oncogene 32, 1752–1760 (2013).

    Article  CAS  PubMed  Google Scholar 

  161. 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  PubMed  PubMed Central  Google Scholar 

  162. [No authors listed] UKCCCR guidelines for the use of cell lines in cancer research. Br. J. Cancer 82, 1495–1509 (2000).

  163. Catena, R. et al. Bone marrow-derived Gr1+ cells can generate a metastasis-resistant microenvironment via induced secretion of thrombospondin-1. Cancer Discov. 3, 578–589 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. El Rayes, T. et al. Lung inflammation promotes metastasis through neutrophil protease-mediated degradation of Tsp-1. Proc. Natl Acad. Sci. USA 112, 16000–16005 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. O'Toole, M. T. Mosby's Medical Dictionary 9th edn (Elsevier/Mosby, 2013).

    Google Scholar 

  166. Guthrie, G. J., Roxburgh, C. S., Farhan-Alanie, O. M., Horgan, P. G. & McMillan, D. C. Comparison of the prognostic value of longitudinal measurements of systemic inflammation in patients undergoing curative resection of colorectal cancer. Br. J. Cancer 109, 24–28 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Santoni, M. et al. Pre-treatment neutrophil-to-lymphocyte ratio may be associated with the outcome in patients treated with everolimus for metastatic renal cell carcinoma. Br. J. Cancer 109, 1755–1759 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Caruso, R. A. et al. Prognostic value of intratumoral neutrophils in advanced gastric carcinoma in a high-risk area in northern Italy. Mod. Pathol. 15, 831–837 (2002).

    Article  PubMed  Google Scholar 

  169. Jensen, H. K. et al. Presence of intratumoral neutrophils is an independent prognostic factor in localized renal cell carcinoma. J. Clin. Oncol. 27, 4709–4717 (2009).

    Article  PubMed  Google Scholar 

  170. Jensen, T. O. et al. Intratumoral neutrophils and plasmacytoid dendritic cells indicate poor prognosis and are associated with pSTAT3 expression in AJCC stage I/II melanoma. Cancer 118, 2476–2485 (2012).

    Article  CAS  PubMed  Google Scholar 

  171. Carus, A. et al. Tumor-associated neutrophils and macrophages in non-small cell lung cancer: no immediate impact on patient outcome. Lung Cancer 81, 130–137 (2013).

    Article  PubMed  Google Scholar 

  172. Droeser, R. A. et al. High myeloperoxidase positive cell infiltration in colorectal cancer is an independent favorable prognostic factor. PLoS ONE 8, e64814 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Rao, H. L. et al. Increased intratumoral neutrophil in colorectal carcinomas correlates closely with malignant phenotype and predicts patients' adverse prognosis. PLoS ONE 7, e30806 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Rennard, S. I. et al. CXCR2 antagonist MK-7123. A phase 2 proof-of-concept trial for chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 191, 1001–1011 (2015).

    Article  CAS  PubMed  Google Scholar 

  175. Bertini, R. et al. Noncompetitive allosteric inhibitors of the inflammatory chemokine receptors CXCR1 and CXCR2: prevention of reperfusion injury. Proc. Natl Acad. Sci. USA 101, 11791–11796 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT02370238 (2015).

  177. US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT02001974 (2015).

  178. Chung, A. S. et al. An interleukin-17-mediated paracrine network promotes tumor resistance to anti-angiogenic therapy. Nat. Med. 19, 1114–1123 (2013).

    Article  CAS  PubMed  Google Scholar 

  179. Shojaei, F. et al. Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells. Nat. Biotechnol. 25, 911–920 (2007).

    Article  CAS  PubMed  Google Scholar 

  180. Shojaei, F. et al. G-CSF-initiated myeloid cell mobilization and angiogenesis mediate tumor refractoriness to anti-VEGF therapy in mouse models. Proc. Natl Acad. Sci. USA 106, 6742–6747 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  181. Phan, V. T. et al. Oncogenic RAS pathway activation promotes resistance to anti-VEGF therapy through G-CSF-induced neutrophil recruitment. Proc. Natl Acad. Sci. USA 110, 6079–6084 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Di Maio, M. et al. Chemotherapy-induced neutropenia and treatment efficacy in advanced non-small-cell lung cancer: a pooled analysis of three randomised trials. Lancet Oncol. 6, 669–677 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  184. Yamanaka, T. et al. Predictive value of chemotherapy-induced neutropenia for the efficacy of oral fluoropyrimidine S-1 in advanced gastric carcinoma. Br. J. Cancer 97, 37–42 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Shitara, K. et al. Neutropaenia as a prognostic factor in metastatic colorectal cancer patients undergoing chemotherapy with first-line FOLFOX. Eur. J. Cancer 45, 1757–1763 (2009).

    Article  CAS  PubMed  Google Scholar 

  186. Coffelt, S. B. & de Visser, K. E. Immune-mediated mechanisms influencing the efficacy of anticancer therapies. Trends Immunol. 36, 198–216 (2015).

    Article  CAS  PubMed  Google Scholar 

  187. Guerriero, J. L. et al. DNA alkylating therapy induces tumor regression through an HMGB1-mediated activation of innate immunity. J. Immunol. 186, 3517–3526 (2011).

    Article  CAS  PubMed  Google Scholar 

  188. Ma, Y. et al. Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells. Immunity 38, 729–741 (2013).

    Article  CAS  PubMed  Google Scholar 

  189. Bruchard, M. et al. Chemotherapy-triggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growth. Nat. Med. 19, 57–64 (2013).

    Article  CAS  PubMed  Google Scholar 

  190. Crawford, J. et al. Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N. Engl. J. Med. 325, 164–170 (1991).

    Article  CAS  PubMed  Google Scholar 

  191. Metcalf, D. The colony-stimulating factors and cancer. Nat. Rev. Cancer 10, 425–434 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Voloshin, T. et al. G-CSF supplementation with chemotherapy can promote revascularization and subsequent tumor regrowth: prevention by a CXCR4 antagonist. Blood 118, 3426–3435 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Deng, L. et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J. Clin. Invest. 124, 687–695 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Ahn, G. O. et al. Inhibition of Mac-1 (CD11b/CD18) enhances tumor response to radiation by reducing myeloid cell recruitment. Proc. Natl Acad. Sci. USA 107, 8363–8368 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Kersten, K., Salvagno, C. & de Visser, K. E. Exploiting the immunomodulatory properties of chemotherapeutic drugs to improve the success of cancer immunotherapy. Front. Immunol. 6, 516 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Postow, M. A. et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N. Engl. J. Med. 372, 2006–2017 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  197. Highfill, S. L. et al. Disruption of CXCR2-mediated MDSC tumor trafficking enhances anti-PD1 efficacy. Sci. Transl Med. 6, 237ra267 (2014).

    Article  CAS  Google Scholar 

  198. Kim, K. et al. Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells. Proc. Natl Acad. Sci. USA 111, 11774–11779 (2014). References 197 and 198 were the first studies to combine checkpoint inhibitors with neutrophil-targeting agents to maximize the efficacy of cancer immunotherapy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Ries, C. H. et al. Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell 25, 846–859 (2014).

    Article  CAS  PubMed  Google Scholar 

  200. Pahler, J. C. et al. Plasticity in tumor-promoting inflammation: impairment of macrophage recruitment evokes a compensatory neutrophil response. Neoplasia 10, 329–340 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Swierczak, A. et al. The promotion of breast cancer metastasis caused by inhibition of CSF-1R/CSF-1 signaling is blocked by targeting the G-CSF receptor. Cancer Immunol. Res. 2, 765–776 (2014).

    Article  CAS  PubMed  Google Scholar 

  202. Rivera, L. B. et al. Intratumoral myeloid cells regulate responsiveness and resistance to antiangiogenic therapy. Cell Rep. 11, 577–591 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Warnatsch, A., Ioannou, M., Wang, Q. & Papayannopoulos, V. Inflammation. Neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis. Science 349, 316–320 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Daley, J. M., Thomay, A. A., Connolly, M. D., Reichner, J. S. & Albina, J. E. Use of Ly6G-specific monoclonal antibody to deplete neutrophils in mice. J. Leukoc. Biol. 83, 64–70 (2008).

    Article  CAS  PubMed  Google Scholar 

  205. Moses, K. et al. Survival of residual neutrophils and accelerated myelopoiesis limit the efficacy of antibody-mediated depletion of Ly6G+ cells in tumor-bearing mice. J. Leukoc. Biol. http://dx.doi.org/10.1189/jlb.1HI0715-289R (2016).

  206. Hasenberg, A. et al. Catchup: a mouse model for imaging-based tracking and modulation of neutrophil granulocytes. Nat. Methods 12, 445–452 (2015). This paper reported a next-generation mouse model that enables the manipulation and imaging of neutrophils in vivo.

    Article  CAS  PubMed  Google Scholar 

  207. Marvel, D. & Gabrilovich, D. I. Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected. J. Clin. Invest. 125, 3356–3364 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  208. Tomihara, K. et al. Antigen-specific immunity and cross-priming by epithelial ovarian carcinoma-induced CD11b+Gr-1+ cells. J. Immunol. 184, 6151–6160 (2010).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors apologize to those whose work they could not cite because of space restrictions. S.B.C. is supported by a Marie Curie Intra-European Fellowship (BMDCMET 275610). Research in the K.d.V lab is supported by a European Research Council Consolidator award (InflaMet 615300), the European Union (FP7 MCA-ITN 317445 TIMCC), the Dutch Cancer Society (2011-5004), Worldwide Cancer Research (AICR 11-0677), the Netherlands Organization for Scientific Research NWO VIDI (917.96.307) and the Beug Foundation for Metastasis Research.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Karin E. de Visser.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

αβ T cells

Most CD4+ and CD8+ T cells are αβ T cells, in which the T cell receptor comprises a heterodimer of an α-chain and a β-chain.

γδ T cells

A small subset of T cells in which the T cell receptor consists of a γ-chain and a δ-chain. These cells behave like innate immune cells and are largely divided into interleukin-17-producing and interferon-γ-producing subsets.

Innate lymphoid cells

Innate immune cells that belong to the lymphoid lineage, but lack antigen-specific receptors.

Neutrophil polarization

A state of neutrophil activation in response to specific cues from its environment, which can promote or limit disease progression.

TH1/TH2

Two major activation states of CD4+ T-helper cells expressing distinct cytokines and exerting different functions. In general, TH1 cells provide immunity against intracellular pathogens, whereas TH2 cells mediate immune responses against extracellular parasites.

M1/M2

Term for macrophage polarization states, in which M1 and M2 represent opposing ends of the macrophage activation spectrum. Historically, M1 represents an antitumour activation state, whereas M2 macrophages are pro-tumoural, although this restrictive nomenclature fails to represent tumour-associated macrophage biology.

N1/N2

Proposed binary classification to distinguish tumour-inhibiting (N1) from tumour-promoting (N2) neutrophils in the cancer setting. However, further evidence to define these polarization states and their relationship to type 1 or type 2 immunity is required before applying this terminology to cancer-associated neutrophils.

Myeloid-derived suppressor cells

A heterogeneous group of immunosuppressive myeloid cells including neutrophils that expand in cancer patients and mouse cancer models.

Autochthonous model

Models of cancer in which tumours arise spontaneously from genetic manipulation or injection of a carcinogen.

Neutrophil extracellular traps

(NETs). Extracellular neutrophil-derived networks of DNA, fibres and various proteins such as elastase and histones. Release of NETs (NETosis) occurs in response to pathogen infection, sterile inflammation and cancer.

Premetastatic niche

A microenvironment in secondary organs primed by the primary tumour that is populated by non-cancer cells and promotes seeding of metastasizing cancer cells.

Regulatory B cells

(Breg cells). A subpopulation of immunosuppressive B cells involved in immunological tolerance.

Secretome

The total secreted factors of a cell or tissue.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Coffelt, S., Wellenstein, M. & de Visser, K. Neutrophils in cancer: neutral no more. Nat Rev Cancer 16, 431–446 (2016). https://doi.org/10.1038/nrc.2016.52

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc.2016.52

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer