Neutrophil diversity and plasticity in tumour progression and therapy

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

Google Scholar 
2.Borregaard, N. Neutrophils, from marrow to microbes. Immunity 33, 657–670 (2010).CAS 
PubMed 

Google Scholar 
3.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).CAS 
PubMed 

Google Scholar 
4.Jaillon, S. et al. Neutrophils in innate and adaptive immunity. Semin. Immunopathol. 35, 377–394 (2013).CAS 
PubMed 

Google Scholar 
5.Scapini, P. & Cassatella, M. A. Social networking of human neutrophils within the immune system. Blood 124, 710–719 (2014).CAS 
PubMed 

Google Scholar 
6.Fridman, W. H., Zitvogel, L., Sautes-Fridman, C. & Kroemer, G. The immune contexture in cancer prognosis and treatment. Nat. Rev. Clin. Oncol. 14, 717–734 (2017).CAS 
PubMed 

Google Scholar 
7.Mantovani, A., Allavena, P., Sica, A. & Balkwill, F. Cancer-related inflammation. Nature 454, 436–444 (2008).CAS 
PubMed 

Google Scholar 
8.Bonavita, E. et al. PTX3 is an extrinsic oncosuppressor regulating complement-dependent inflammation in cancer. Cell 160, 700–714 (2015).CAS 
PubMed 

Google Scholar 
9.Grivennikov, S. I., Greten, F. R. & Karin, M. Immunity, inflammation, and cancer. Cell 140, 883–899 (2010).CAS 
PubMed 
PubMed Central 

Google Scholar 
10.Mantovani, A., Marchesi, F., Malesci, A., Laghi, L. & Allavena, P. Tumour-associated macrophages as treatment targets in oncology. Nat. Rev. Clin. Oncol. 14, 399–416 (2017).CAS 
PubMed 
PubMed Central 

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

Google Scholar 
12.Shaul, M. E. & Fridlender, Z. G. Tumour-associated neutrophils in patients with cancer. Nat. Rev. Clin. Oncol. 16, 601–620 (2019).PubMed 

Google Scholar 
13.Galdiero, M. R. et al. Occurrence and significance of tumor-associated neutrophils in patients with colorectal cancer. Int. J. Cancer 139, 446–456 (2016).CAS 
PubMed 

Google Scholar 
14.Gentles, A. J. et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat. Med. 21, 938–945 (2015). This paper shows that a neutrophil signature is associated with adverse prognosis in most solid tumours.CAS 
PubMed 
PubMed Central 

Google Scholar 
15.Ponzetta, A. et al. Neutrophils driving unconventional T cells mediate resistance against murine sarcomas and selected human tumors. Cell 178, 346–360.e24 (2019). This study demonstrates a tripartite interaction between neutrophils, macrophages and a subset of T cells, UTCαβ, essential for the establishment of effective antitumour immunity in select tumours.CAS 
PubMed 
PubMed Central 

Google Scholar 
16.Kargl, J. et al. Neutrophils dominate the immune cell composition in non-small cell lung cancer. Nat. Commun. 8, 14381 (2017).CAS 
PubMed 
PubMed Central 

Google Scholar 
17.Petitprez, F. et al. B cells are associated with survival and immunotherapy response in sarcoma. Nature 577, 556–560 (2020).CAS 
PubMed 

Google Scholar 
18.Ng, L. G., Ostuni, R. & Hidalgo, A. Heterogeneity of neutrophils. Nat. Rev. Immunol. 19, 255–265 (2019).CAS 
PubMed 

Google Scholar 
19.Nemeth, T., Sperandio, M. & Mocsai, A. Neutrophils as emerging therapeutic targets. Nat. Rev. Drug Discov. 19, 253–275 (2020).CAS 
PubMed 

Google Scholar 
20.Eruslanov, E. B., Singhal, S. & Albelda, S. M. Mouse versus human neutrophils in cancer: a major knowledge gap. Trends Cancer 3, 149–160 (2017).CAS 
PubMed 
PubMed Central 

Google Scholar 
21.Mestas, J. & Hughes, C. C. Of mice and not men: differences between mouse and human immunology. J. Immunol. 172, 2731–2738 (2004).CAS 
PubMed 

Google Scholar 
22.Lawrence, S. M., Corriden, R. & Nizet, V. The ontogeny of a neutrophil: mechanisms of granulopoiesis and homeostasis. Microbiol. Mol. Biol. Rev. 82, e00057-17 (2018).PubMed 
PubMed Central 

Google Scholar 
23.Skokowa, J. et al. Interactions among HCLS1, HAX1 and LEF-1 proteins are essential for G-CSF-triggered granulopoiesis. Nat. Med. 18, 1550–1559 (2012).CAS 
PubMed 
PubMed Central 

Google Scholar 
24.Zeidler, C., Germeshausen, M., Klein, C. & Welte, K. Clinical implications of ELA2-, HAX1-, and G-CSF-receptor (CSF3R) mutations in severe congenital neutropenia. Br. J. Haematol. 144, 459–467 (2009).CAS 
PubMed 

Google Scholar 
25.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).CAS 
PubMed 

Google Scholar 
26.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 
27.Romani, L. et al. Impaired neutrophil response and CD4+ T helper cell 1 development in interleukin 6-deficient mice infected with Candida albicans. J. Exp. Med. 183, 1345–1355 (1996).CAS 
PubMed 

Google Scholar 
28.Walker, F. et al. IL6/sIL6R complex contributes to emergency granulopoietic responses in G-CSF- and GM-CSF-deficient mice. Blood 111, 3978–3985 (2008).CAS 
PubMed 

Google Scholar 
29.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).CAS 
PubMed 
PubMed Central 

Google Scholar 
30.Casanova-Acebes, M. et al. Rhythmic modulation of the hematopoietic niche through neutrophil clearance. Cell 153, 1025–1035 (2013).CAS 
PubMed 
PubMed Central 

Google Scholar 
31.Zhang, D. et al. Neutrophil ageing is regulated by the microbiome. Nature 525, 528–532 (2015).CAS 
PubMed 
PubMed Central 

Google Scholar 
32.Adrover, J. M. et al. A neutrophil timer coordinates immune defense and vascular protection. Immunity 50, 390–402.e10 (2019). Together with reference 31, this paper identifies extrinsic and intrinsic mechanisms involved in the process of neutrophil ageing.CAS 
PubMed 

Google Scholar 
33.Stark, M. A. et al. Phagocytosis of apoptotic neutrophils regulates granulopoiesis via IL-23 and IL-17. Immunity 22, 285–294 (2005).CAS 
PubMed 

Google Scholar 
34.Casanova-Acebes, M. et al. Neutrophils instruct homeostatic and pathological states in naive tissues. J. Exp. Med. 215, 2778–2795 (2018).CAS 
PubMed 
PubMed Central 

Google Scholar 
35.Coffelt, S. B. et al. IL-17-producing γδ T cells and neutrophils conspire to promote breast cancer metastasis. Nature 522, 345–348 (2015). This study demonstrates that neutrophils orchestrate systemic inflammation to promote metastasis.CAS 
PubMed 
PubMed Central 

Google Scholar 
36.Wellenstein, M. D. et al. Loss of p53 triggers WNT-dependent systemic inflammation to drive breast cancer metastasis. Nature 572, 538–542 (2019). This paper demonstrates that a WNT–IL-1β axis leads to neutrophil expansion and the subsequent formation of breast cancer metastases.CAS 
PubMed 
PubMed Central 

Google Scholar 
37.Jin, C. et al. Commensal microbiota promote lung cancer development via γδ T cells. Cell 176, 998–1013.e16 (2019).CAS 
PubMed 
PubMed Central 

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

Google Scholar 
39.Mollica Poeta, V., Massara, M., Capucetti, A. & Bonecchi, R. Chemokines and chemokine receptors: new targets for cancer immunotherapy. Front. Immunol. 10, 379 (2019).PubMed 
PubMed Central 

Google Scholar 
40.Jamieson, T. et al. Inhibition of CXCR2 profoundly suppresses inflammation-driven and spontaneous tumorigenesis. J. Clin. Invest. 122, 3127–3144 (2012).CAS 
PubMed 
PubMed Central 

Google Scholar 
41.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).CAS 
PubMed 
PubMed Central 

Google Scholar 
42.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 
43.Raccosta, L. et al. The oxysterol–CXCR2 axis plays a key role in the recruitment of tumor-promoting neutrophils. J. Exp. Med. 210, 1711–1728 (2013).CAS 
PubMed 
PubMed Central 

Google Scholar 
44.Roumenina, L. T., Daugan, M. V., Petitprez, F., Sautes-Fridman, C. & Fridman, W. H. Context-dependent roles of complement in cancer. Nat. Rev. Cancer 19, 698–715 (2019).CAS 
PubMed 

Google Scholar 
45.Reis, E. S., Mastellos, D. C., Ricklin, D., Mantovani, A. & Lambris, J. D. Complement in cancer: untangling an intricate relationship. Nat. Rev. Immunol. 18, 5–18 (2018).CAS 
PubMed 

Google Scholar 
46.Sody, S. et al. Distinct spatio-temporal dynamics of tumor-associated neutrophils in small tumor lesions. Front. Immunol. 10, 1419 (2019).CAS 
PubMed 
PubMed Central 

Google Scholar 
47.Patel, S. et al. Unique pattern of neutrophil migration and function during tumor progression. Nat. Immunol. 19, 1236–1247 (2018). This study highlights functional changes that neutrophils undergo during tumour progression and demonstrates that immunosuppressive activity is limited to neutrophils from the late stages of cancer.CAS 
PubMed 
PubMed Central 

Google Scholar 
48.Granot, Z. et al. Tumor entrained neutrophils inhibit seeding in the premetastatic lung. Cancer Cell 20, 300–314 (2011).CAS 
PubMed 
PubMed Central 

Google Scholar 
49.Massara, M. et al. ACKR2 in hematopoietic precursors as a checkpoint of neutrophil release and anti-metastatic activity. Nat. Commun. 9, 676 (2018).PubMed 
PubMed Central 

Google Scholar 
50.Wculek, S. K. & Malanchi, I. Neutrophils support lung colonization of metastasis-initiating breast cancer cells. Nature 528, 413–417 (2015).CAS 
PubMed 
PubMed Central 

Google Scholar 
51.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 
PubMed 

Google Scholar 
52.Acharyya, S. et al. A CXCL1 paracrine network links cancer chemoresistance and metastasis. Cell 150, 165–178 (2012).CAS 
PubMed 
PubMed Central 

Google Scholar 
53.Wu, F. Y. et al. Chemokine decoy receptor d6 plays a negative role in human breast cancer. Mol. Cancer Res. 6, 1276–1288 (2008).CAS 
PubMed 

Google Scholar 
54.Adrover, J. M. et al. Programmed ‘disarming’ of the neutrophil proteome reduces the magnitude of inflammation. Nat. Immunol. 21, 135–144 (2020). This article demonstrates the homeostatic degranulation and ‘disarming’ of neutrophils driven by regulators of circadian cycles.CAS 
PubMed 
PubMed Central 

Google Scholar 
55.Xie, X. et al. Single-cell transcriptome profiling reveals neutrophil heterogeneity and orchestrated maturation during homeostasis and bacterial infection. Preprint at bioRxiv https://doi.org/10.1101/792200v1 (2019).56.Zilionis, R. et al. Single-cell transcriptomics of human and mouse lung cancers reveals conserved myeloid populations across individuals and species. Immunity 50, 1317–1334.e10 (2019). This study identifies populations of tumour-infiltrating myeloid cells in human and mouse lung tumours.CAS 
PubMed 
PubMed Central 

Google Scholar 
57.Puga, I. et al. B cell-helper neutrophils stimulate the diversification and production of immunoglobulin in the marginal zone of the spleen. Nat. Immunol. 13, 170–180 (2011).PubMed 
PubMed Central 

Google Scholar 
58.Lok, L. S. C. et al. Phenotypically distinct neutrophils patrol uninfected human and mouse lymph nodes. Proc. Natl Acad. Sci. USA 116, 19083–19089 (2019).CAS 
PubMed 

Google Scholar 
59.Locati, M., Curtale, G. & Mantovani, A. Diversity, mechanisms, and significance of macrophage plasticity. Annu. Rev. Pathol. 15, 123–147 (2020).CAS 
PubMed 

Google Scholar 
60.Alshetaiwi, H. et al. Defining the emergence of myeloid-derived suppressor cells in breast cancer using single-cell transcriptomics. Sci. Immunol. 5, eaay6017 (2020).CAS 
PubMed 

Google Scholar 
61.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 
PubMed 

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

Google Scholar 
63.Zhu, Y. P. et al. Identification of an early unipotent neutrophil progenitor with pro-tumoral activity in mouse and human bone marrow. Cell Rep. 24, 2329–2341.e8 (2018).CAS 
PubMed 
PubMed Central 

Google Scholar 
64.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 paper demonstrates the polarization of TANs induced by TGFβ signalling.CAS 
PubMed 
PubMed Central 

Google Scholar 
65.Shaul, M. E. et al. Tumor-associated neutrophils display a distinct N1 profile following TGFβ modulation: a transcriptomics analysis of pro- vs. antitumor TANs. Oncoimmunology 5, e1232221 (2016).PubMed 
PubMed Central 

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

Google Scholar 
67.Andzinski, L. et al. Type I IFNs induce anti-tumor polarization of tumor associated neutrophils in mice and human. Int. J. Cancer 138, 1982–1993 (2016).CAS 
PubMed 

Google Scholar 
68.Singhal, S. et al. Origin and role of a subset of tumor-associated neutrophils with antigen-presenting cell features in early-stage human lung cancer. Cancer Cell 30, 120–135 (2016).CAS 
PubMed 
PubMed Central 

Google Scholar 
69.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).PubMed 
PubMed Central 

Google Scholar 
70.Si, Y. et al. Multidimensional imaging provides evidence for down-regulation of T cell effector function by MDSC in human cancer tissue. Sci. Immunol. 4, eaaw9159 (2019).CAS 
PubMed 

Google Scholar 
71.Granot, Z. & Fridlender, Z. G. Plasticity beyond cancer cells and the “immunosuppressive switch”. Cancer Res. 75, 4441–4445 (2015).CAS 
PubMed 

Google Scholar 
72.Butin-Israeli, V. et al. Neutrophil-induced genomic instability impedes resolution of inflammation and wound healing. J. Clin. Invest. 129, 712–726 (2019).PubMed 
PubMed Central 

Google Scholar 
73.Gungor, N. et al. Genotoxic effects of neutrophils and hypochlorous acid. Mutagenesis 25, 149–154 (2010).PubMed 

Google Scholar 
74.Wilson, C. L. et al. NFκB1 is a suppressor of neutrophil-driven hepatocellular carcinoma. Nat. Commun. 6, 6818 (2015).CAS 
PubMed 
PubMed Central 

Google Scholar 
75.Granot, Z. & Jablonska, J. Distinct functions of neutrophil in cancer and its regulation. Mediators Inflamm. 2015, 701067 (2015).PubMed 
PubMed Central 

Google Scholar 
76.Tecchio, C., Scapini, P., Pizzolo, G. & Cassatella, M. A. On the cytokines produced by human neutrophils in tumors. Semin. Cancer Biol. 23, 159–170 (2013).CAS 
PubMed 

Google Scholar 
77.Houghton, A. M. et al. Neutrophil elastase-mediated degradation of IRS-1 accelerates lung tumor growth. Nat. Med. 16, 219–223 (2010).CAS 
PubMed 
PubMed Central 

Google Scholar 
78.Lerman, I. et al. Infiltrating myeloid cells exert protumorigenic actions via neutrophil elastase. Mol. Cancer Res. 15, 1138–1152 (2017).CAS 
PubMed 
PubMed Central 

Google Scholar 
79.Caruso, J. A., Akli, S., Pageon, L., Hunt, K. K. & Keyomarsi, K. The serine protease inhibitor elafin maintains normal growth control by opposing the mitogenic effects of neutrophil elastase. Oncogene 34, 3556–3567 (2015).CAS 
PubMed 

Google Scholar 
80.Wada, Y. et al. Neutrophil elastase induces cell proliferation and migration by the release of TGF-α, PDGF and VEGF in esophageal cell lines. Oncol. Rep. 17, 161–167 (2007).CAS 
PubMed 

Google Scholar 
81.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).CAS 
PubMed 

Google Scholar 
82.Scapini, P. et al. CXCL1/macrophage inflammatory protein-2-induced angiogenesis in vivo is mediated by neutrophil-derived vascular endothelial growth factor-A. J. Immunol. 172, 5034–5040 (2004).CAS 
PubMed 

Google Scholar 
83.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).CAS 
PubMed 

Google Scholar 
84.Albini, A., Bruno, A., Noonan, D. M. & Mortara, L. Contribution to tumor angiogenesis from innate immune cells within the tumor microenvironment: implications for immunotherapy. Front. Immunol. 9, 527 (2018).PubMed 
PubMed Central 

Google Scholar 
85.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).CAS 
PubMed 

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

Google Scholar 
87.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).CAS 
PubMed 

Google Scholar 
88.Tohme, S. et al. Neutrophil extracellular traps promote the development and progression of liver metastases after surgical stress. Cancer Res. 76, 1367–1380 (2016).CAS 
PubMed 
PubMed Central 

Google Scholar 
89.Guglietta, S. et al. Coagulation induced by C3aR-dependent NETosis drives protumorigenic neutrophils during small intestinal tumorigenesis. Nat. Commun. 7, 11037 (2016).CAS 
PubMed 
PubMed Central 

Google Scholar 
90.Albrengues, J. et al. Neutrophil extracellular traps produced during inflammation awaken dormant cancer cells in mice. Science 361, eaao4227 (2018). This study demonstrates that proteolytic cleavage of the extracellular matrix protein laminin by proteases contained in NETs reveals a new epitope that triggers proliferation of cancer cells.PubMed 
PubMed Central 

Google Scholar 
91.Park, J. et al. Cancer cells induce metastasis-supporting neutrophil extracellular DNA traps. Sci. Transl. Med. 8, 361ra138 (2016).PubMed 
PubMed Central 

Google Scholar 
92.van der Windt, D. J. et al. Neutrophil extracellular traps promote inflammation and development of hepatocellular carcinoma in nonalcoholic steatohepatitis. Hepatology 68, 1347–1360 (2018).PubMed 
PubMed Central 

Google Scholar 
93.Cools-Lartigue, J. et al. Neutrophil extracellular traps sequester circulating tumor cells and promote metastasis. J. Clin. Invest. 123, 3446–3458 (2013).CAS 
PubMed Central 

Google Scholar 
94.Rayes, R. F. et al. Primary tumors induce neutrophil extracellular traps with targetable metastasis promoting effects. JCI Insight 5, e128008 (2019).
Google Scholar 
95.Aldabbous, L. et al. Neutrophil extracellular traps promote angiogenesis: evidence from vascular pathology in pulmonary hypertension. Arterioscler. Thromb. Vasc. Biol. 36, 2078–2087 (2016).CAS 
PubMed 

Google Scholar 
96.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).CAS 
PubMed 

Google Scholar 
97.Jackstadt, R. et al. Epithelial NOTCH signaling rewires the tumor microenvironment of colorectal cancer to drive poor-prognosis subtypes and metastasis. Cancer Cell 36, 319–336.e7 (2019).CAS 
PubMed 
PubMed Central 

Google Scholar 
98.Chen, M. B. et al. Inflamed neutrophils sequestered at entrapped tumor cells via chemotactic confinement promote tumor cell extravasation. Proc. Natl Acad. Sci. USA 115, 7022–7027 (2018).CAS 
PubMed 

Google Scholar 
99.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 
PubMed 
PubMed Central 

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

Google Scholar 
101.Szczerba, B. M. et al. Neutrophils escort circulating tumour cells to enable cell cycle progression. Nature 566, 553–557 (2019). This paper highlights that CTCs associated with neutrophils acquire a proliferative advantage.CAS 
PubMed 

Google Scholar 
102.Ghajar, C. M. et al. The perivascular niche regulates breast tumour dormancy. Nat. Cell Biol. 15, 807–817 (2013).CAS 
PubMed 
PubMed Central 

Google Scholar 
103.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).CAS 
PubMed 
PubMed Central 

Google Scholar 
104.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).CAS 
PubMed 

Google Scholar 
105.Mensurado, S. et al. Tumor-associated neutrophils suppress pro-tumoral IL-17+ γδ T cells through induction of oxidative stress. PLoS Biol. 16, e2004990 (2018).PubMed 
PubMed Central 

Google Scholar 
106.Schmielau, J. & Finn, O. J. Activated granulocytes and granulocyte-derived hydrogen peroxide are the underlying mechanism of suppression of T-cell function in advanced cancer patients. Cancer Res. 61, 4756–4760 (2001).CAS 
PubMed 

Google Scholar 
107.Rice, C. M. et al. Tumour-elicited neutrophils engage mitochondrial metabolism to circumvent nutrient limitations and maintain immune suppression. Nat. Commun. 9, 5099 (2018).PubMed 
PubMed Central 

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

Google Scholar 
109.Rodriguez, P. C. et al. Arginase I-producing myeloid-derived suppressor cells in renal cell carcinoma are a subpopulation of activated granulocytes. Cancer Res. 69, 1553–1560 (2009).CAS 
PubMed 
PubMed Central 

Google Scholar 
110.Liu, C. Y. et al. Population alterations of l-arginase- and inducible nitric oxide synthase-expressed CD11b+/CD14–/CD15+/CD33+ myeloid-derived suppressor cells and CD8+ T lymphocytes in patients with advanced-stage non-small cell lung cancer. J. Cancer Res. Clin. Oncol. 136, 35–45 (2010).CAS 
PubMed 

Google Scholar 
111.O’Neill, L. A. & Pearce, E. J. Immunometabolism governs dendritic cell and macrophage function. J. Exp. Med. 213, 15–23 (2016).PubMed 
PubMed Central 

Google Scholar 
112.Cubillos-Ruiz, J. R. et al. ER stress sensor XBP1 controls anti-tumor immunity by disrupting dendritic cell homeostasis. Cell 161, 1527–1538 (2015).CAS 
PubMed 
PubMed Central 

Google Scholar 
113.Al-Khami, A. A. et al. Exogenous lipid uptake induces metabolic and functional reprogramming of tumor-associated myeloid-derived suppressor cells. Oncoimmunology 6, e1344804 (2017).PubMed 
PubMed Central 

Google Scholar 
114.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).PubMed 
PubMed Central 

Google Scholar 
115.Veglia, F. et al. Fatty acid transport protein 2 reprograms neutrophils in cancer. Nature 569, 73–78 (2019). This paper shows that overexpression of FATP2 in neutrophils promotes the synthesis of PGE
2and the subsequent immunosuppressive activity.CAS 
PubMed 
PubMed Central 

Google Scholar 
116.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 
PubMed 
PubMed Central 

Google Scholar 
117.Noman, M. Z. et al. PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J. Exp. Med. 211, 781–790 (2014).CAS 
PubMed 
PubMed Central 

Google Scholar 
118.de Kleijn, S. et al. IFN-γ-stimulated neutrophils suppress lymphocyte proliferation through expression of PD-L1. PLoS ONE 8, e72249 (2013).PubMed 
PubMed Central 

Google Scholar 
119.Cheng, Y. et al. Cancer-associated fibroblasts induce PDL1+ neutrophils through the IL6–STAT3 pathway that foster immune suppression in hepatocellular carcinoma. Cell Death Dis. 9, 422 (2018).PubMed 
PubMed Central 

Google Scholar 
120.Wang, T. T. et al. Tumour-activated neutrophils in gastric cancer foster immune suppression and disease progression through GM-CSF–PD-L1 pathway. Gut 66, 1900–1911 (2017).CAS 
PubMed 
PubMed Central 

Google Scholar 
121.He, G. et al. Peritumoural neutrophils negatively regulate adaptive immunity via the PD-L1/PD-1 signalling pathway in hepatocellular carcinoma. J. Exp. Clin. Cancer Res. 34, 141 (2015).PubMed 
PubMed Central 

Google Scholar 
122.Xu, W. et al. Immune-checkpoint protein VISTA regulates antitumor immunity by controlling myeloid cell-mediated inflammation and immunosuppression. Cancer Immunol. Res. 7, 1497–1510 (2019).PubMed 
PubMed Central 

Google Scholar 
123.Wang, L. et al. VISTA, a novel mouse Ig superfamily ligand that negatively regulates T cell responses. J. Exp. Med. 208, 577–592 (2011).CAS 
PubMed 
PubMed Central 

Google Scholar 
124.Molgora, M. et al. The yin–yang of the interaction between myelomonocytic cells and NK cells. Scand. J. Immunol. 88, e12705 (2018).PubMed 
PubMed Central 

Google Scholar 
125.Benigni, G. et al. CXCR3/CXCL10 axis regulates neutrophil–NK cell cross-talk determining the severity of experimental osteoarthritis. J. Immunol. 198, 2115–2124 (2017).CAS 
PubMed 

Google Scholar 
126.Spiegel, A. et al. Neutrophils suppress intraluminal NK cell-mediated tumor cell clearance and enhance extravasation of disseminated carcinoma cells. Cancer Discov. 6, 630–649 (2016).CAS 
PubMed 
PubMed Central 

Google Scholar 
127.Teijeira, A. et al. CXCR1 and CXCR2 chemokine receptor agonists produced by tumors induce neutrophil extracellular traps that interfere with immune cytotoxicity. Immunity 52, 856–871 e858 (2020). This paper shows that NETs can protect tumour cells from immune cytotoxicity.CAS 
PubMed 

Google Scholar 
128.Tumino, N. et al. PMN-MDSC are a new target to rescue graft-versus-leukemia activity of NK cells in haplo-HSC transplantation. Leukemia 34, 932–937 (2019).PubMed 
PubMed Central 

Google Scholar 
129.Ogura, K. et al. NK cells control tumor-promoting function of neutrophils in mice. Cancer Immunol. Res. 6, 348–357 (2018).CAS 
PubMed 

Google Scholar 
130.Ueda, R. et al. Interaction of natural killer cells with neutrophils exerts a significant antitumor immunity in hematopoietic stem cell transplantation recipients. Cancer Med. 5, 49–60 (2016).CAS 
PubMed 

Google Scholar 
131.Colombo, M. P. et al. Granulocyte colony-stimulating factor gene transfer suppresses tumorigenicity of a murine adenocarcinoma in vivo. J. Exp. Med. 173, 889–897 (1991).CAS 
PubMed 

Google Scholar 
132.Blaisdell, A. et al. Neutrophils oppose uterine epithelial carcinogenesis via debridement of hypoxic tumor cells. Cancer Cell 28, 785–799 (2015).CAS 
PubMed 
PubMed Central 

Google Scholar 
133.Mahiddine, K. et al. Relief of tumor hypoxia unleashes the tumoricidal potential of neutrophils. J. Clin. Invest. 130, 389–403 (2020).CAS 
PubMed 

Google Scholar 
134.Gershkovitz, M. et al. TRPM2 mediates neutrophil killing of disseminated tumor cells. Cancer Res. 78, 2680–2690 (2018). This study demonstrates the mechanism responsible for the cytotoxic activity of neutrophil-derived ROS towards cancer cells.CAS 
PubMed 

Google Scholar 
135.Gershkovitz, M., Fainsod-Levi, T., Zelter, T., Sionov, R. V. & Granot, Z. TRPM2 modulates neutrophil attraction to murine tumor cells by regulating CXCL2 expression. Cancer Immunol. Immunother. 68, 33–43 (2019).PubMed 

Google Scholar 
136.Finisguerra, V. et al. MET is required for the recruitment of anti-tumoural neutrophils. Nature 522, 349–353 (2015).CAS 
PubMed 
PubMed Central 

Google Scholar 
137.Koga, Y., Matsuzaki, A., Suminoe, A., Hattori, H. & Hara, T. Neutrophil-derived TNF-related apoptosis-inducing ligand (TRAIL): a novel mechanism of antitumor effect by neutrophils. Cancer Res. 64, 1037–1043 (2004).CAS 
PubMed 

Google Scholar 
138.Glodde, N. et al. Reactive neutrophil responses dependent on the receptor tyrosine kinase c-MET limit cancer immunotherapy. Immunity 47, 789–802.e9 (2017).CAS 
PubMed 

Google Scholar 
139.Hagerling, C. et al. Immune effector monocyte–neutrophil cooperation induced by the primary tumor prevents metastatic progression of breast cancer. Proc. Natl Acad. Sci. USA 116, 21704–21714 (2019).CAS 
PubMed 

Google Scholar 
140.Fridlender, Z. G. et al. Transcriptomic analysis comparing tumor-associated neutrophils with granulocytic myeloid-derived suppressor cells and normal neutrophils. PLoS ONE 7, e31524 (2012).CAS 
PubMed 
PubMed Central 

Google Scholar 
141.Governa, V. et al. The interplay between neutrophils and CD8+ T cells improves survival in human colorectal cancer. Clin. Cancer Res. 23, 3847–3858 (2017).CAS 
PubMed 

Google Scholar 
142.Grivennikov, S. I. et al. Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. Nature 491, 254–258 (2012).CAS 
PubMed 
PubMed Central 

Google Scholar 
143.Brennan, C. A. & Garrett, W. S. Gut microbiota, inflammation, and colorectal cancer. Annu. Rev. Microbiol. 70, 395–411 (2016).CAS 
PubMed 
PubMed Central 

Google Scholar 
144.Dmitrieva-Posocco, O. et al. Cell-type-specific responses to interleukin-1 control microbial invasion and tumor-elicited inflammation in colorectal cancer. Immunity 50, 166–180.e7 (2019). This study shows that IL-1 signalling in neutrophils has tumour-suppressive activity through the control of microbiota-induced inflammation.CAS 
PubMed 
PubMed Central 

Google Scholar 
145.Triner, D. et al. Neutrophils restrict tumor-associated microbiota to reduce growth and invasion of colon tumors in mice. Gastroenterology 156, 1467–1482 (2019).PubMed 

Google Scholar 
146.Colombo, M. P. et al. Granulocyte colony-stimulating factor (G-CSF) gene transduction in murine adenocarcinoma drives neutrophil-mediated tumor inhibition in vivo. Neutrophils discriminate between G-CSF-producing and G-CSF-nonproducing tumor cells. J. Immunol. 149, 113–119 (1992).CAS 
PubMed 

Google Scholar 
147.Liu, Y. et al. CD11b+Ly6G+ cells inhibit tumor growth by suppressing IL-17 production at early stages of tumorigenesis. Oncoimmunology 5, e1061175 (2016).PubMed 

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

Google Scholar 
149.Zhu, Y. P. et al. CyTOF reveals phenotypically-distinct human blood neutrophil populations differentially correlated with melanoma stage. Preprint at bioRxiv https://doi.org/10.1101/826644v2 (2019).150.Marini, O. et al. Mature CD10+ and immature CD10– neutrophils present in G-CSF-treated donors display opposite effects on T cells. Blood 129, 1343–1356 (2017).CAS 
PubMed 

Google Scholar 
151.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).PubMed 

Google Scholar 
152.Vano, Y. A. et al. Optimal cut-off for neutrophil-to-lymphocyte ratio: fact or fantasy? A prospective cohort study in metastatic cancer patients. PLoS ONE 13, e0195042 (2018).PubMed 
PubMed Central 

Google Scholar 
153.Ivars Rubio, A. et al. Neutrophil–lymphocyte ratio in metastatic breast cancer is not an independent predictor of survival, but depends on other variables. Sci. Rep. 9, 16979 (2019).PubMed 
PubMed Central 

Google Scholar 
154.Polidoro, M. A. et al. Impact of RAS mutations on the immune infiltrate of colorectal liver metastases: a preliminary study. J. Leukoc. Biol. https://doi.org/10.1002/JLB.5AB0220-608R (2020).Article 
PubMed 

Google Scholar 
155.Kuang, D. M. et al. Peritumoral neutrophils link inflammatory response to disease progression by fostering angiogenesis in hepatocellular carcinoma. J. Hepatol. 54, 948–955 (2011).CAS 
PubMed 

Google Scholar 
156.Bindea, G. et al. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity 39, 782–795 (2013).CAS 
PubMed 

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

Google Scholar 
158.Zhou, G. et al. CD177+ neutrophils suppress epithelial cell tumourigenesis in colitis-associated cancer and predict good prognosis in colorectal cancer. Carcinogenesis 39, 272–282 (2018).CAS 
PubMed 

Google Scholar 
159.Zhang, H. et al. Tumor-infiltrating neutrophils is prognostic and predictive for postoperative adjuvant chemotherapy benefit in patients with gastric cancer. Ann. Surg. 267, 311–318 (2018).PubMed 

Google Scholar 
160.Posabella, A. et al. High density of CD66b in primary high-grade ovarian cancer independently predicts response to chemotherapy. J. Cancer Res. Clin. Oncol. 146, 127–136 (2020).CAS 
PubMed 

Google Scholar 
161.Pylaeva, E. et al. NAMPT signaling is critical for the proangiogenic activity of tumor-associated neutrophils. Int. J. Cancer 144, 136–149 (2019).CAS 
PubMed 

Google Scholar 
162.Shrestha, S. et al. Angiotensin converting enzyme inhibitors and angiotensin II receptor antagonist attenuate tumor growth via polarization of neutrophils toward an antitumor phenotype. Oncoimmunology 5, e1067744 (2016).PubMed 

Google Scholar 
163.Yang, J. et al. Loss of CXCR4 in myeloid cells enhances antitumor immunity and reduces melanoma growth through NK cell and FASL mechanisms. Cancer Immunol. Res. 6, 1186–1198 (2018).CAS 
PubMed 
PubMed Central 

Google Scholar 
164.Matlung, H. L. et al. Neutrophils kill antibody-opsonized cancer cells by trogoptosis. Cell Rep. 23, 3946–3959.e6 (2018). This paper shows that blockade of the CD47–SIRPα checkpoint interaction increases the cytotoxic activity of neutrophils towards antibody-opsonized cancer cells.CAS 
PubMed 

Google Scholar 
165.Chao, M. P. et al. Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma. Cell 142, 699–713 (2010).CAS 
PubMed 
PubMed Central 

Google Scholar 
166.Ring, N. G. et al. Anti-SIRPα antibody immunotherapy enhances neutrophil and macrophage antitumor activity. Proc. Natl Acad. Sci. USA 114, E10578–E10585 (2017).CAS 
PubMed 

Google Scholar 
167.Chen, H. M. et al. Blocking immunoinhibitory receptor LILRB2 reprograms tumor-associated myeloid cells and promotes antitumor immunity. J. Clin. Invest. 128, 5647–5662 (2018).PubMed 
PubMed Central 

Google Scholar 
168.Steele, C. W. et al. CXCR2 inhibition profoundly suppresses metastases and augments immunotherapy in pancreatic ductal adenocarcinoma. Cancer Cell 29, 832–845 (2016).CAS 
PubMed 
PubMed Central 

Google Scholar 
169.Schalper, K. A. et al. Elevated serum interleukin-8 is associated with enhanced intratumor neutrophils and reduced clinical benefit of immune-checkpoint inhibitors. Nat. Med. 26, 688–692 (2020).CAS 
PubMed 

Google Scholar 
170.Yuen, K. C. et al. High systemic and tumor-associated IL-8 correlates with reduced clinical benefit of PD-L1 blockade. Nat. Med. 26, 693–698 (2020).CAS 
PubMed 

Google Scholar 
171.US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT03400332 (2018).172.US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT03689699 (2018).173.Bilusic, M. et al. Phase I trial of HuMax-IL8 (BMS-986253), an anti-IL-8 monoclonal antibody, in patients with metastatic or unresectable solid tumors. J. Immunother. Cancer 7, 240 (2019).PubMed 
PubMed Central 

Google Scholar 
174.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).CAS 
PubMed 

Google Scholar 
175.US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT03177187 (2017).176.US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT01861054 (2013).177.Schott, A. F. et al. Phase Ib pilot study to evaluate reparixin in combination with weekly paclitaxel in patients with HER-2-negative metastatic breast cancer. Clin. Cancer Res. 23, 5358–5365 (2017).CAS 
PubMed 
PubMed Central 

Google Scholar 
178.US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02001974 (2013).179.US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02370238 (2015).180.US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03161431 (2017).181.US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03473925 (2018).182.Schall, T. J. & Proudfoot, A. E. Overcoming hurdles in developing successful drugs targeting chemokine receptors. Nat. Rev. Immunol. 11, 355–363 (2011).CAS 
PubMed 

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

Google Scholar 
184.Brandsma, A. M. et al. Potent Fc receptor signaling by IgA leads to superior killing of cancer cells by neutrophils compared to IgG. Front. Immunol. 10, 704 (2019).CAS 
PubMed 
PubMed Central 

Google Scholar 
185.Pascal, V. et al. Anti-CD20 IgA can protect mice against lymphoma development: evaluation of the direct impact of IgA and cytotoxic effector recruitment on CD20 target cells. Haematologica 97, 1686–1694 (2012).CAS 
PubMed 
PubMed Central 

Google Scholar 
186.Treffers, L. W. et al. IgA-mediated killing of tumor cells by neutrophils is enhanced by CD47–SIRPα checkpoint inhibition. Cancer Immunol. Res. 8, 120–130 (2020).CAS 
PubMed 

Google Scholar 
187.Otten, M. A. et al. Enhanced FcαRI-mediated neutrophil migration towards tumour colonies in the presence of endothelial cells. Eur. J. Immunol. 42, 1815–1821 (2012).CAS 
PubMed 

Google Scholar 
188.Feng, M. et al. Phagocytosis checkpoints as new targets for cancer immunotherapy. Nat. Rev. Cancer 19, 568–586 (2019).CAS 
PubMed 
PubMed Central 

Google Scholar 
189.Casey, S. C. et al. MYC regulates the antitumor immune response through CD47 and PD-L1. Science 352, 227–231 (2016).CAS 
PubMed 
PubMed Central 

Google Scholar 
190.Advani, R. et al. CD47 blockade by Hu5F9-G4 and rituximab in non-Hodgkin’s lymphoma. N. Engl. J. Med. 379, 1711–1721 (2018).CAS 
PubMed 

Google Scholar 
191.Baudhuin, J. et al. Exocytosis acts as a modulator of the ILT4-mediated inhibition of neutrophil functions. Proc. Natl Acad. Sci. USA 110, 17957–17962 (2013).CAS 
PubMed 

Google Scholar 
192.Mantovani, A. & Longo, D. L. Macrophage checkpoint blockade in cancer—back to the future. N. Engl. J. Med. 379, 1777–1779 (2018).PubMed 

Google Scholar 
193.McCracken, M. N., Cha, A. C. & Weissman, I. L. Molecular pathways: activating T cells after cancer cell phagocytosis from blockade of CD47 “don’t eat me” signals. Clin. Cancer Res. 21, 3597–3601 (2015).CAS 
PubMed 
PubMed Central 

Google Scholar 
194.Tseng, D. et al. Anti-CD47 antibody-mediated phagocytosis of cancer by macrophages primes an effective antitumor T-cell response. Proc. Natl Acad. Sci. USA 110, 11103–11108 (2013).CAS 
PubMed 

Google Scholar 
195.Liu, X. et al. CD47 blockade triggers T cell-mediated destruction of immunogenic tumors. Nat. Med. 21, 1209–1215 (2015).CAS 
PubMed 
PubMed Central 

Google Scholar 
196.Soto-Pantoja, D. R. et al. CD47 in the tumor microenvironment limits cooperation between antitumor T-cell immunity and radiotherapy. Cancer Res. 74, 6771–6783 (2014).CAS 
PubMed 
PubMed Central 

Google Scholar 
197.Georgoudaki, A. M. et al. Reprogramming tumor-associated macrophages by antibody targeting inhibits cancer progression and metastasis. Cell Rep. 15, 2000–2011 (2016).CAS 
PubMed 

Google Scholar 
198.Viitala, M. et al. Immunotherapeutic blockade of macrophage clever-1 reactivates the CD8+ T-cell response against immunosuppressive tumors. Clin. Cancer Res. 25, 3289–3303 (2019).PubMed 

Google Scholar 
199.Nakamura, K. & Smyth, M. J. Myeloid immunosuppression and immune checkpoints in the tumor microenvironment. Cell Mol. Immunol. 17, 1–12 (2020).CAS 
PubMed 

Google Scholar 
200.Mantovani, A. Reflections on immunological nomenclature: in praise of imperfection. Nat. Immunol. 17, 215–216 (2016).CAS 
PubMed 

Google Scholar 
201.Dinarello, C. et al. IL-1 family nomenclature. Nat. Immunol. 11, 973 (2010).CAS 
PubMed 
PubMed Central 

Google Scholar 
202.Murray, P. J. et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41, 14–20 (2014).CAS 
PubMed 
PubMed Central 

Google Scholar 
203.Spits, H. et al. Innate lymphoid cells—a proposal for uniform nomenclature. Nat. Rev. Immunol. 13, 145–149 (2013).CAS 
PubMed 

Google Scholar 
204.Chua, W., Charles, K. A., Baracos, V. E. & Clarke, S. J. Neutrophil/lymphocyte ratio predicts chemotherapy outcomes in patients with advanced colorectal cancer. Br. J. Cancer 104, 1288–1295 (2011).CAS 
PubMed 
PubMed Central 

Google Scholar 
205.Cha, Y. J., Park, E. J., Baik, S. H., Lee, K. Y. & Kang, J. Clinical significance of tumor-infiltrating lymphocytes and neutrophil-to-lymphocyte ratio in patients with stage III colon cancer who underwent surgery followed by FOLFOX chemotherapy. Sci. Rep. 9, 11617 (2019).PubMed 
PubMed Central 

Google Scholar 
206.Dell’Aquila, E. et al. Prognostic and predictive role of neutrophil/lymphocytes ratio in metastatic colorectal cancer: a retrospective analysis of the TRIBE study by GONO. Ann. Oncol. 29, 924–930 (2018).PubMed 

Google Scholar 
207.Chen, Y. et al. Pretreatment neutrophil-to-lymphocyte ratio is correlated with response to neoadjuvant chemotherapy as an independent prognostic indicator in breast cancer patients: a retrospective study. BMC Cancer 16, 320 (2016).PubMed 
PubMed Central 

Google Scholar 
208.Xu, J. et al. Association of neutrophil/lymphocyte ratio and platelet/lymphocyte ratio with ER and PR in breast cancer patients and their changes after neoadjuvant chemotherapy. Clin. Transl. Oncol. 19, 989–996 (2017).CAS 
PubMed 

Google Scholar 
209.Chae, S. et al. Neutrophil–lymphocyte ratio predicts response to chemotherapy in triple-negative breast cancer. Curr. Oncol. 25, e113–e119 (2018).CAS 
PubMed 
PubMed Central 

Google Scholar 
210.Cassidy, M. R. et al. Neutrophil to lymphocyte ratio is associated with outcome during ipilimumab treatment. EBioMedicine 18, 56–61 (2017).PubMed 
PubMed Central 

Google Scholar 
211.Capone, M. et al. Baseline neutrophil-to-lymphocyte ratio (NLR) and derived NLR could predict overall survival in patients with advanced melanoma treated with nivolumab. J. Immunother. Cancer 6, 74 (2018).PubMed 
PubMed Central 

Google Scholar 
212.Ferrucci, P. F. et al. Baseline neutrophil-to-lymphocyte ratio is associated with outcome of ipilimumab-treated metastatic melanoma patients. Br. J. Cancer 112, 1904–1910 (2015).CAS 
PubMed 
PubMed Central 

Google Scholar 
213.Schmidt, H. et al. Pretreatment levels of peripheral neutrophils and leukocytes as independent predictors of overall survival in patients with American Joint Committee on Cancer stage IV melanoma: results of the EORTC 18951 biochemotherapy trial. J. Clin. Oncol. 25, 1562–1569 (2007).CAS 
PubMed 

Google Scholar 
214.Zaragoza, J. et al. High neutrophil to lymphocyte ratio measured before starting ipilimumab treatment is associated with reduced overall survival in patients with melanoma. Br. J. Dermatol. 174, 146–151 (2016).CAS 
PubMed 

Google Scholar 
215.Khoja, L. et al. The full blood count as a biomarker of outcome and toxicity in ipilimumab-treated cutaneous metastatic melanoma. Cancer Med. 5, 2792–2799 (2016).CAS 
PubMed 
PubMed Central 

Google Scholar 
216.Jung, M. et al. Ipilimumab real-world efficacy and safety in Korean melanoma patients from the Korean named-patient program cohort. Cancer Res. Treat. 49, 44–53 (2017).CAS 
PubMed 

Google Scholar 
217.Rosner, S. et al. Peripheral blood clinical laboratory variables associated with outcomes following combination nivolumab and ipilimumab immunotherapy in melanoma. Cancer Med. 7, 690–697 (2018).CAS 
PubMed 
PubMed Central 

Google Scholar 
218.Cho, H. et al. Pre-treatment neutrophil to lymphocyte ratio is elevated in epithelial ovarian cancer and predicts survival after treatment. Cancer Immunol. Immunother. 58, 15–23 (2009).CAS 
PubMed 

Google Scholar 
219.Wisdom, A. J. et al. Neutrophils promote tumor resistance to radiation therapy. Proc. Natl Acad. Sci. USA 116, 18584–18589 (2019).CAS 
PubMed 

Google Scholar 
220.Amato, R. J., Xiong, Y., Peng, H. & Mohlere, V. Clinical outcomes model in renal cell cancer patients treated with modified vaccinia Ankara plus tumor-associated antigen 5T4. Int. J. Biol. Markers 30, e111–e121 (2015).CAS 
PubMed 

Google Scholar 
221.Bilen, M. A. et al. Association between pretreatment neutrophil-to-lymphocyte ratio and outcome of patients with metastatic renal-cell carcinoma treated with nivolumab. Clin. Genitourin. Cancer 16, e563–e575 (2018).PubMed 
PubMed Central 

Google Scholar 
222.Sharaiha, R. Z. et al. Elevated preoperative neutrophil:lymphocyte ratio as a predictor of postoperative disease recurrence in esophageal cancer. Ann. Surg. Oncol. 18, 3362–3369 (2011).PubMed 
PubMed Central 

Google Scholar 
223.Fukui, T. et al. Activity of nivolumab and utility of neutrophil-to-lymphocyte ratio as a predictive biomarker for advanced non-small-cell lung cancer: a prospective observational study. Clin. Lung Cancer 20, 208–214.e2 (2019).CAS 
PubMed 

Google Scholar 
224.Diem, S. et al. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) as prognostic markers in patients with non-small cell lung cancer (NSCLC) treated with nivolumab. Lung Cancer 111, 176–181 (2017).PubMed 

Google Scholar 
225.Bagley, S. J. et al. Pretreatment neutrophil-to-lymphocyte ratio as a marker of outcomes in nivolumab-treated patients with advanced non-small-cell lung cancer. Lung Cancer 106, 1–7 (2017).PubMed 

Google Scholar 
226.Shiroyama, T. et al. Pretreatment advanced lung cancer inflammation index (ALI) for predicting early progression in nivolumab-treated patients with advanced non-small cell lung cancer. Cancer Med. 7, 13–20 (2018).CAS 
PubMed 

Google Scholar 
227.Nakaya, A. et al. Neutrophil-to-lymphocyte ratio as an early marker of outcomes in patients with advanced non-small-cell lung cancer treated with nivolumab. Int. J. Clin. Oncol. 23, 634–640 (2018).CAS 
PubMed 
PubMed Central 

Google Scholar 
228.Russo, A. et al. Baseline neutrophilia, derived neutrophil-to-lymphocyte ratio (dNLR), platelet-to-lymphocyte ratio (PLR), and outcome in non small cell lung cancer (NSCLC) treated with nivolumab or docetaxel. J. Cell Physiol. 233, 6337–6343 (2018).CAS 
PubMed 
PubMed Central 

Google Scholar 
229.Tanizaki, J. et al. Peripheral blood biomarkers associated with clinical outcome in non-small cell lung cancer patients treated with nivolumab. J. Thorac. Oncol. 13, 97–105 (2018).CAS 
PubMed 

Google Scholar 
230.Koinis, F. et al. Effect of first-line treatment on myeloid-derived suppressor cells’ subpopulations in the peripheral blood of patients with non-small cell lung cancer. J. Thorac. Oncol. 11, 1263–1272 (2016).PubMed 

Google Scholar 
231.Liu, Z. L. et al. Neutrophil–lymphocyte ratio as a prognostic marker for chemotherapy in advanced lung cancer. Int. J. Biol. Markers 31, e395–e401 (2016).CAS 
PubMed 

Google Scholar 
232.Schernberg, A., Blanchard, P., Chargari, C. & Deutsch, E. Neutrophils, a candidate biomarker and target for radiation therapy? Acta Oncol. 56, 1522–1530 (2017).CAS 
PubMed 

Google Scholar 
233.Xie, X. et al. Prognostic value of baseline neutrophil-to-lymphocyte ratio in outcome of immune checkpoint inhibitors. Cancer Invest. 37, 265–274 (2019).CAS 
PubMed 

Google Scholar 
234.Sacdalan, D. B., Lucero, J. A. & Sacdalan, D. L. Prognostic utility of baseline neutrophil-to-lymphocyte ratio in patients receiving immune checkpoint inhibitors: a review and meta-analysis. Onco Targets Ther. 11, 955–965 (2018).PubMed 
PubMed Central 

Google Scholar 
235.Schiffmann, L. M. et al. Tumour-infiltrating neutrophils counteract anti-VEGF therapy in metastatic colorectal cancer. Br. J. Cancer 120, 69–78 (2019).CAS 
PubMed 

Google Scholar 
236.Wang, J. et al. Tumor-infiltrating neutrophils predict prognosis and adjuvant chemotherapeutic benefit in patients with biliary cancer. Cancer Sci. 109, 2266–2274 (2018).CAS 
PubMed 
PubMed Central 

Google Scholar 
237.Kargl, J. et al. Neutrophil content predicts lymphocyte depletion and anti-PD1 treatment failure in NSCLC. JCI Insight 4, e130850 (2019).PubMed Central 

Google Scholar 
238.Manfroi, B. et al. Tumor-associated neutrophils correlate with poor prognosis in diffuse large B-cell lymphoma patients. Blood Cancer J. 8, 66 (2018).CAS 
PubMed 
PubMed Central 

Google Scholar 
239.Zhou, S. L. et al. Tumor-associated neutrophils recruit macrophages and T-regulatory cells to promote progression of hepatocellular carcinoma and resistance to sorafenib. Gastroenterology 150, 1646–1658.e17 (2016).CAS 
PubMed 

Google Scholar 
240.Matsumoto, Y. et al. The significance of tumor-associated neutrophil density in uterine cervical cancer treated with definitive radiotherapy. Gynecol. Oncol. 145, 469–475 (2017).PubMed 

Google Scholar 
241.Wang, J., Shiratori, I., Uehori, J., Ikawa, M. & Arase, H. Neutrophil infiltration during inflammation is regulated by PILRα via modulation of integrin activation. Nat. Immunol. 14, 34–40 (2013).CAS 
PubMed 

Google Scholar 
242.Strauss, L. et al. Targeted deletion of PD-1 in myeloid cells induces antitumor immunity. Sci. Immunol. 5, eaay1863 (2020).CAS 
PubMed 
PubMed Central 

Google Scholar 
243.Jenmalm, M. C., Cherwinski, H., Bowman, E. P., Phillips, J. H. & Sedgwick, J. D. Regulation of myeloid cell function through the CD200 receptor. J. Immunol. 176, 191–199 (2006).CAS 
PubMed 

Google Scholar 
244.Casulli, J. et al. CD200R deletion promotes a neutrophil niche for Francisella tularensis and increases infectious burden and mortality. Nat. Commun. 10, 2121 (2019).CAS 
PubMed 
PubMed Central 

Google Scholar 
245.Boxio, R., Bossenmeyer-Pourie, C., Steinckwich, N., Dournon, C. & Nusse, O. Mouse bone marrow contains large numbers of functionally competent neutrophils. J. Leukoc. Biol. 75, 604–611 (2004).CAS 
PubMed 

Google Scholar 
246.Paul, F. et al. Transcriptional heterogeneity and lineage commitment in myeloid progenitors. Cell 163, 1663–1677 (2015).CAS 
PubMed 

Google Scholar 
247.Grassi, L. et al. Dynamics of transcription regulation in human bone marrow myeloid differentiation to mature blood neutrophils. Cell Rep. 24, 2784–2794 (2018).CAS 
PubMed 
PubMed Central 

Google Scholar 
248.Giladi, A. et al. Single-cell characterization of haematopoietic progenitors and their trajectories in homeostasis and perturbed haematopoiesis. Nat. Cell Biol. 20, 836–846 (2018).CAS 
PubMed 

Google Scholar 
249.Evrard, M. et al. Developmental analysis of bone marrow neutrophils reveals populations specialized in expansion, trafficking, and effector functions. Immunity 48, 364–379.e8 (2018). This study identifies populations of N
Iin the bone marrow using mass cytometry.CAS 
PubMed 

Google Scholar 
250.Shaul, M. E. et al. Circulating neutrophil subsets in advanced lung cancer patients exhibit unique immune signature and relate to prognosis. FASEB J. 34, 4204–4218 (2020).CAS 
PubMed 

Google Scholar 
251.Engblom, C. et al. Osteoblasts remotely supply lung tumors with cancer-promoting SiglecFhigh neutrophils. Science 358, eaal5081 (2017).PubMed 
PubMed Central 

Google Scholar 
252.Lee, P. Y., Wang, J. X., Parisini, E., Dascher, C. C. & Nigrovic, P. A. Ly6 family proteins in neutrophil biology. J. Leukoc. Biol. 94, 585–594 (2013).CAS 
PubMed 

Google Scholar 
253.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).CAS 
PubMed 

Google Scholar 
254.Faget, J. et al. Efficient and specific Ly6G+ cell depletion: a change in the current practices toward more relevant functional analyses of neutrophils. Preprint at bioRxiv https://doi.org/10.1101/498881v1 (2018).255.Moses, K. et al. Survival of residual neutrophils and accelerated myelopoiesis limit the efficacy of antibody-mediated depletion of Ly-6G+ cells in tumor-bearing mice. J. Leukoc. Biol. 99, 811–823 (2016).CAS 
PubMed 

Google Scholar 
256.Bruhn, K. W., Dekitani, K., Nielsen, T. B., Pantapalangkoor, P. & Spellberg, B. Ly6G-mediated depletion of neutrophils is dependent on macrophages. Results Immunol. 6, 5–7 (2016).PubMed 

Google Scholar 
257.Gael Boivin, G. et al. Durable and controlled depletion of neutrophils in mice. Nat. Commun. 11, 2762 (2020).PubMed 
PubMed Central 

Google Scholar 
258.Csepregi, J. Z. et al. Myeloid-specific deletion of Mcl-1 yields severely neutropenic mice that survive and breed in homozygous form. J. Immunol. 201, 3793–3803 (2018).CAS 
PubMed 
PubMed Central 

Google Scholar 
259.Stackowicz, J., Jonsson, F. & Reber, L. L. Mouse models and tools for the in vivo study of neutrophils. Front. Immunol. 10, 3130 (2019).PubMed 

Google Scholar 
260.Dzhagalov, I., St John, A. & He, Y. W. The antiapoptotic protein Mcl-1 is essential for the survival of neutrophils but not macrophages. Blood 109, 1620–1626 (2007).CAS 
PubMed 
PubMed Central 

Google Scholar 
261.Hasenberg, A. et al. Catchup: a mouse model for imaging-based tracking and modulation of neutrophil granulocytes. Nat. Methods 12, 445–452 (2015).CAS 
PubMed 

Google Scholar 
262.Romero-Moreno, R. et al. The CXCL5/CXCR2 axis is sufficient to promote breast cancer colonization during bone metastasis. Nat. Commun. 10, 4404 (2019).PubMed 
PubMed Central 

Google Scholar 
263.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).CAS 
PubMed 

Google Scholar 
264.Purohit, A. et al. CXCR2 signaling regulates KRAS(G12D)-induced autocrine growth of pancreatic cancer. Oncotarget 7, 7280–7296 (2016).PubMed 
PubMed Central 

Google Scholar 
265.Saintigny, P. et al. CXCR2 expression in tumor cells is a poor prognostic factor and promotes invasion and metastasis in lung adenocarcinoma. Cancer Res. 73, 571–582 (2013).CAS 
PubMed 

Google Scholar 
266.Di Mitri, D. et al. Re-education of tumor-associated macrophages by CXCR2 blockade drives senescence and tumor inhibition in advanced prostate cancer. Cell Rep. 28, 2156–2168.e5 (2019).PubMed 
PubMed Central 

Google Scholar 

Read More