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Protumor and antitumor functions of neutrophil granulocytes

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Abstract

Neutrophils are primary inflammatory cells and absolutely essential to protect the host during the early phases of microbial infection. Their role in cancer is less clear. Current evidence suggests that neutrophils show high functional plasticity and can adopt protumor and antitumor activity. Protumor neutrophils are functionally related to the recently described granulocytic myeloid-derived suppressor cells. We propose a model in which homeostatic chronic recruitment and activation of neutrophils result in mainly protumor activity. In contrast, therapeutic interventions in many cases elicit acute activation, enhance direct effector functions as well as indirect regulatory functions of neutrophils with potent antitumor activity. Conversion of protumor activity of neutrophils into antitumor activity by means of appropriate stimulation or modulation may offer new possibilities in biologic therapy of cancer.

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References

  1. Schreiber RD, Old LJ, Smyth MJ (2011) Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331:1565–1570

    Article  PubMed  CAS  Google Scholar 

  2. Faurschou M, Borregaard N (2003) Neutrophil granules and secretory vesicles in inflammation. Microbes Infect 5:1317–1327

    Article  PubMed  CAS  Google Scholar 

  3. Nathan C (2006) Neutrophils and immunity: challenges and opportunities. Nat Rev Immunol 6:173–182

    Article  PubMed  CAS  Google Scholar 

  4. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  6. Halazun KJ, Hardy MA, Rana AA, Woodland DC, Luyten EJ, Mahadev S, Witkowski P, Siegel AB, Brown RS Jr, Emond JC (2009) Negative impact of neutrophil-lymphocyte ratio on outcome after liver transplantation for hepatocellular carcinoma. Ann Surg 250:141–151

    Article  PubMed  Google Scholar 

  7. He JR, Shen GP, Ren ZF, Qin H, Cui C, Zhang Y, Zeng YX, Jia WH (2012) Pretreatment levels of peripheral neutrophils and lymphocytes as independent prognostic factors in patients with nasopharyngeal carcinoma. Head Neck. doi:10.1002/hed.22008 [Epub ahead of print]

  8. Jensen HK, Donskov F, Marcussen N, Nordsmark M, Lundbeck F, von der Maase H (2009) Presence of intratumoral neutrophils is an independent prognostic factor in localized renal cell carcinoma. J Clin Oncol 27:4709–4717

    Article  PubMed  Google Scholar 

  9. Schmidt H, Bastholt L, Geertsen P, Christensen IJ, Larsen S, Gehl J, von der Maase H (2005) Elevated neutrophil and monocyte counts in peripheral blood are associated with poor survival in patients with metastatic melanoma: a prognostic model. Br J Cancer 93:273–278

    Article  PubMed  CAS  Google Scholar 

  10. Walsh SR, Cook EJ, Goulder F, Justin TA, Keeling NJ (2005) Neutrophil-lymphocyte ratio as a prognostic factor in colorectal cancer. J Surg Oncol 91:181–184

    Article  PubMed  CAS  Google Scholar 

  11. Dumitru CA, Moses K, Trellakis S, Lang S, Brandau S (2012) Neutrophils and granulocytic myeloid-derived suppressor cells: immunophenotyping, cell biology and clinical relevance in human oncology. Cancer Immunol Immunother 61(8):1155–1167

    Article  PubMed  CAS  Google Scholar 

  12. Almand B, Clark JI, Nikitina E, van Beynen J, English NR, Knight SC, Carbone DP, Gabrilovich DI (2001) Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J Immunol 166:678–689

    PubMed  CAS  Google Scholar 

  13. Trellakis S, Farjah H, Bruderek K, Dumitru CA, Hoffmann TK, Lang S, Brandau S (2011) Peripheral blood neutrophil granulocytes from patients with head and neck squamous cell carcinoma functionally differ from their counterparts in healthy donors. Int J Immunopathol Pharmacol 24:683–693

    PubMed  CAS  Google Scholar 

  14. Brandau S, Trellakis S, Bruderek K, Schmaltz D, Steller G, Elian M, Suttmann H, Schenck M, Welling J, Zabel P, Lang S (2011) Myeloid-derived suppressor cells in the peripheral blood of cancer patients contain a subset of immature neutrophils with impaired migratory properties. J Leukoc Biol 89:311–317

    Article  PubMed  CAS  Google Scholar 

  15. Choi J, Suh B, Ahn YO, Kim TM, Lee JO, Lee SH, Heo DS (2012) CD15+/CD16low human granulocytes from terminal cancer patients: granulocytic myeloid-derived suppressor cells that have suppressive function. Tumour Biol 33:121–129

    Article  PubMed  CAS  Google Scholar 

  16. Cortez-Retamozo V, Etzrodt M, Newton A, Rauch PJ, Chudnovskiy A, Berger C, Ryan RJ, Iwamoto Y, Marinelli B, Gorbatov R, Forghani R, Novobrantseva TI, Koteliansky V, Figueiredo JL, Chen JW, Anderson DG, Nahrendorf M, Swirski FK, Weissleder R, Pittet MJ (2012) Origins of tumor-associated macrophages and neutrophils. Proc Natl Acad Sci U S A 109:2491–2496

    Article  PubMed  CAS  Google Scholar 

  17. Gabrilovich DI, Velders MP, Sotomayor EM, Kast WM (2001) Mechanism of immune dysfunction in cancer mediated by immature Gr-1+ myeloid cells. J Immunol 166:5398–5406

    PubMed  CAS  Google Scholar 

  18. Youn JI, Gabrilovich DI (2010) The biology of myeloid-derived suppressor cells: the blessing and the curse of morphological and functional heterogeneity. Eur J Immunol 40:2969–2975

    Article  PubMed  CAS  Google Scholar 

  19. Gabrilovich DI, Bronte V, Chen SH, Colombo MP, Ochoa A, Ostrand-Rosenberg S, Schreiber H (2007) The terminology issue for myeloid-derived suppressor cells. Cancer Res 67:425

    Article  PubMed  CAS  Google Scholar 

  20. Montero AJ, Diaz-Montero CM, Kyriakopoulos CE, Bronte V, Mandruzzato S (2012) Myeloid-derived suppressor cells in cancer patients: a clinical perspective. J Immunother 35:107–115

    Article  PubMed  Google Scholar 

  21. Nagaraj S, Gabrilovich DI (2010) Myeloid-derived suppressor cells in human cancer. Cancer J 16:348–353

    Article  PubMed  CAS  Google Scholar 

  22. Ostrand-Rosenberg S, Sinha P (2009) Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol 182:4499–4506

    Article  PubMed  CAS  Google Scholar 

  23. Youn JI, Collazo M, Shalova IN, Biswas SK, Gabrilovich DI (2012) Characterization of the nature of granulocytic myeloid-derived suppressor cells in tumor-bearing mice. J Leukoc Biol 91:167–181

    Article  PubMed  CAS  Google Scholar 

  24. Fridlender ZG, Sun J, Mishalian I, Singhal S, Cheng G, Kapoor V, Horng W, Fridlender G, Bayuh R, Worthen GS, Albelda SM (2012) Transcriptomic analysis comparing tumor-associated neutrophils with granulocytic myeloid-derived suppressor cells and normal neutrophils. PLoS One 7:e31524

    Article  PubMed  CAS  Google Scholar 

  25. Ribechini E, Greifenberg V, Sandwick S, Lutz MB (2010) Subsets, expansion and activation of myeloid-derived suppressor cells. Med Microbiol Immunol 199:273–281

    Article  PubMed  CAS  Google Scholar 

  26. Condamine T, Gabrilovich DI (2011) Molecular mechanisms regulating myeloid-derived suppressor cell differentiation and function. Trends Immunol 32:19–25

    Article  PubMed  CAS  Google Scholar 

  27. Gabrilovich DI, Ostrand-Rosenberg S, Bronte V (2012) Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol 12:253–268

    Article  PubMed  CAS  Google Scholar 

  28. Basu S, Dunn A, Ward A (2002) G-CSF: function and modes of action (Review). Int J Mol Med 10:3–10

    PubMed  CAS  Google Scholar 

  29. Waight JD, Hu Q, Miller A, Liu S, Abrams SI (2011) Tumor-derived G-CSF facilitates neoplastic growth through a granulocytic myeloid-derived suppressor cell-dependent mechanism. PLoS One 6:e27690

    Article  PubMed  CAS  Google Scholar 

  30. Roberts AW (2005) G-CSF: a key regulator of neutrophil production, but that’s not all! Growth Factors 23:33–41

    Article  PubMed  CAS  Google Scholar 

  31. Berliner N, Hsing A, Graubert T, Sigurdsson F, Zain M, Bruno E, Hoffman R (1995) Granulocyte colony-stimulating factor induction of normal human bone marrow progenitors results in neutrophil-specific gene expression. Blood 85:799–803

    PubMed  CAS  Google Scholar 

  32. Lechner MG, Liebertz DJ, Epstein AL (2010) Characterization of cytokine-induced myeloid-derived suppressor cells from normal human peripheral blood mononuclear cells. J Immunol 185:2273–2284

    Article  PubMed  CAS  Google Scholar 

  33. Solito S, Falisi E, Diaz-Montero CM, Doni A, Pinton L, Rosato A, Francescato S, Basso G, Zanovello P, Onicescu G, Garrett-Mayer E, Montero AJ, Bronte V, Mandruzzato S (2011) A human promyelocytic-like population is responsible for the immune suppression mediated by myeloid-derived suppressor cells. Blood 118:2254–2265

    Article  PubMed  CAS  Google Scholar 

  34. Joshita S, Nakazawa K, Sugiyama Y, Kamijo A, Matsubayashi K, Miyabayashi H, Furuta K, Kitano K, Kawa S (2009) Granulocyte-colony stimulating factor-producing pancreatic adenosquamous carcinoma showing aggressive clinical course. Intern Med 48:687–691

    Article  PubMed  Google Scholar 

  35. Nakada T, Sato H, Inoue F, Mizorogi F, Nagayama K, Tanaka T (1996) The production of colony-stimulating factors by thyroid carcinoma is associated with marked neutrophilia and eosinophilia. Intern Med 35:815–820

    Article  PubMed  CAS  Google Scholar 

  36. Matsumoto Y, Mabuchi S, Muraji M, Morii E, Kimura T (2010) Squamous cell carcinoma of the uterine cervix producing granulocyte colony-stimulating factor: a report of 4 cases and a review of the literature. Int J Gynecol Cancer 20:417–421

    Article  PubMed  Google Scholar 

  37. Corzo CA, Condamine T, Lu L, Cotter MJ, Youn JI, Cheng P, Cho HI, Celis E, Quiceno DG, Padhya T, McCaffrey TV, McCaffrey JC, Gabrilovich DI (2010) HIF-1alpha regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J Exp Med 207:2439–2453

    Article  PubMed  CAS  Google Scholar 

  38. Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867

    Article  PubMed  CAS  Google Scholar 

  39. Lazennec G, Richmond A (2010) Chemokines and chemokine receptors: new insights into cancer-related inflammation. Trends Mol Med 16:133–144

    Article  PubMed  CAS  Google Scholar 

  40. Hannelien V, Karel G, Jo VD, Sofie S (2012) The role of CXC chemokines in the transition of chronic inflammation to esophageal and gastric cancer. Biochim Biophys Acta 1825:117–129

    PubMed  Google Scholar 

  41. Waugh DJ, Wilson C (2008) The interleukin-8 pathway in cancer. Clin Cancer Res 14:6735–6741

    Article  PubMed  CAS  Google Scholar 

  42. Zhou SL, Dai Z, Zhou ZJ, Wang XY, Yang GH, Wang Z, Huang XW, Fan J, Zhou J (2012) Overexpression of CXCL5 mediates neutrophil infiltration and indicates poor prognosis for hepatocellular carcinoma. Hepatology. doi:10.1002/hep.25907 [Epub ahead of print]

  43. Okabe H, Beppu T, Ueda M, Hayashi H, Ishiko T, Masuda T, Otao R, Horlad H, Mima K, Miyake K, Iwatsuki M, Baba Y, Takamori H, Jono H, Shinriki S, Ando Y, Baba H (2012) Identification of CXCL5/ENA-78 as a factor involved in the interaction between cholangiocarcinoma cells and cancer-associated fibroblasts. Int J Cancer. doi:10.1002/ijc.27496 [Epub ahead of print]

  44. Gao Q, Zhao YJ, Wang XY, Qiu SJ, Shi YH, Sun J, Yi Y, Shi JY, Shi GM, Ding ZB, Xiao YS, Zhao ZH, Zhou J, He XH, Fan J (2012) CXCR6 upregulation contributes to a proinflammatory tumor microenvironment that drives metastasis and poor patient outcomes in hepatocellular carcinoma. Cancer Res 72(14):3546–3556

    Article  PubMed  CAS  Google Scholar 

  45. Trellakis S, Bruderek K, Dumitru CA, Gholaman H, Gu X, Bankfalvi A, Scherag A, Hutte J, Dominas N, Lehnerdt GF, Hoffmann TK, Lang S, Brandau S (2011) Polymorphonuclear granulocytes in human head and neck cancer: enhanced inflammatory activity, modulation by cancer cells and expansion in advanced disease. Int J Cancer 129:2183–2193

    Article  PubMed  CAS  Google Scholar 

  46. Bernhagen J, Krohn R, Lue H, Gregory JL, Zernecke A, Koenen RR, Dewor M, Georgiev I, Schober A, Leng L, Kooistra T, Fingerle-Rowson G, Ghezzi P, Kleemann R, McColl SR, Bucala R, Hickey MJ, Weber C (2007) MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. Nat Med 13:587–596

    Article  PubMed  CAS  Google Scholar 

  47. Dumitru CA, Gholaman H, Trellakis S, Bruderek K, Dominas N, Gu X, Bankfalvi A, Whiteside TL, Lang S, Brandau S (2011) Tumor-derived macrophage migration inhibitory factor modulates the biology of head and neck cancer cells via neutrophil activation. Int J Cancer 129:859–869

    Article  PubMed  CAS  Google Scholar 

  48. Florey O, Haskard DO (2009) Sphingosine 1-phosphate enhances Fc gamma receptor-mediated neutrophil activation and recruitment under flow conditions. J Immunol 183:2330–2336

    Article  PubMed  CAS  Google Scholar 

  49. Gault CR, Obeid LM (2011) Still benched on its way to the bedside: sphingosine kinase 1 as an emerging target in cancer chemotherapy. Crit Rev Biochem Mol Biol 46:342–351

    Article  PubMed  CAS  Google Scholar 

  50. Jamieson NB, Carter CR, McKay CJ, Oien KA (2011) Tissue biomarkers for prognosis in pancreatic ductal adenocarcinoma: a systematic review and meta-analysis. Clin Cancer Res 17:3316–3331

    Article  PubMed  CAS  Google Scholar 

  51. Tang D, Kang R, Zeh HJ III, Lotze MT (2010) High-mobility group box 1 and cancer. Biochim Biophys Acta 1799:131–140

    Article  PubMed  CAS  Google Scholar 

  52. Orlova VV, Choi EY, Xie C, Chavakis E, Bierhaus A, Ihanus E, Ballantyne CM, Gahmberg CG, Bianchi ME, Nawroth PP, Chavakis T (2007) A novel pathway of HMGB1-mediated inflammatory cell recruitment that requires Mac-1-integrin. EMBO J 26:1129–1139

    Article  PubMed  CAS  Google Scholar 

  53. Ryckman C, Vandal K, Rouleau P, Talbot M, Tessier PA (2003) Proinflammatory activities of S100: proteins S100A8, S100A9, and S100A8/A9 induce neutrophil chemotaxis and adhesion. J Immunol 170:3233–3242

    PubMed  CAS  Google Scholar 

  54. Zhao JJ, Pan K, Wang W, Chen JG, Wu YH, Lv L, Li JJ, Chen YB, Wang DD, Pan QZ, Li XD, Xia JC (2012) The prognostic value of tumor-infiltrating neutrophils in gastric adenocarcinoma after resection. PLoS One 7:e33655

    Article  PubMed  CAS  Google Scholar 

  55. Rao HL, Chen JW, Li M, Xiao YB, Fu J, Zeng YX, Cai MY, Xie D (2012) Increased intratumoral neutrophil in colorectal carcinomas correlates closely with malignant phenotype and predicts patients’ adverse prognosis. PLoS One 7:e30806

    Article  PubMed  CAS  Google Scholar 

  56. Nozawa H, Chiu C, Hanahan D (2006) Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proc Natl Acad Sci U S A 103:12493–12498

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  58. Bekes EM, Schweighofer B, Kupriyanova TA, Zajac E, Ardi VC, Quigley JP, Deryugina EI (2011) 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

    Article  PubMed  CAS  Google Scholar 

  59. Dumitru CA, Fechner MK, Hoffmann TK, Lang S, Brandau S (2012) A novel p38-MAPK signaling axis modulates neutrophil biology in head and neck cancer. J Leukoc Biol 91:591–598

    Article  PubMed  CAS  Google Scholar 

  60. Kuang DM, Zhao Q, Wu Y, Peng C, Wang J, Xu Z, Yin XY, Zheng L (2011) Peritumoral neutrophils link inflammatory response to disease progression by fostering angiogenesis in hepatocellular carcinoma. J Hepatol 54:948–955

    Article  PubMed  CAS  Google Scholar 

  61. Wu Y, Zhao Q, Peng C, Sun L, Li XF, Kuang DM (2011) Neutrophils promote motility of cancer cells via a hyaluronan-mediated TLR4/PI3K activation loop. J Pathol 225:438–447

    Article  PubMed  CAS  Google Scholar 

  62. Strell C, Lang K, Niggemann B, Zaenker KS, Entschladen F (2010) Neutrophil granulocytes promote the migratory activity of MDA-MB-468 human breast carcinoma cells via ICAM-1. Exp Cell Res 316:138–148

    Article  PubMed  CAS  Google Scholar 

  63. Shamamian P, Schwartz JD, Pocock BJ, Monea S, Whiting D, Marcus SG, Mignatti P (2001) Activation of progelatinase A (MMP-2) by neutrophil elastase, cathepsin G, and proteinase-3: a role for inflammatory cells in tumor invasion and angiogenesis. J Cell Physiol 189:197–206

    Article  PubMed  CAS  Google Scholar 

  64. Queen MM, Ryan RE, Holzer RG, Keller-Peck CR, Jorcyk CL (2005) Breast cancer cells stimulate neutrophils to produce oncostatin M: potential implications for tumor progression. Cancer Res 65:8896–8904

    Article  PubMed  CAS  Google Scholar 

  65. Imai Y, Kubota Y, Yamamoto S, Tsuji K, Shimatani M, Shibatani N, Takamido S, Matsushita M, Okazaki K (2005) Neutrophils enhance invasion activity of human cholangiocellular carcinoma and hepatocellular carcinoma cells: an in vitro study. J Gastroenterol Hepatol 20:287–293

    Article  PubMed  CAS  Google Scholar 

  66. Tazawa H, Okada F, Kobayashi T, Tada M, Mori Y, Une Y, Sendo F, Kobayashi M, Hosokawa M (2003) 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

    Article  PubMed  CAS  Google Scholar 

  67. Spicer JD, McDonald B, Cools-Lartigue JJ, Chow SC, Giannias B, Kubes P, Ferri LE (2012) Neutrophils promote liver metastasis via Mac-1 mediated interactions with circulating tumor cells. Cancer Res 72(16):3919–3927. doi:10.1158/0008-5472.CAN-11-2393

    Article  PubMed  CAS  Google Scholar 

  68. Psaila B, Lyden D (2009) The metastatic niche: adapting the foreign soil. Nat Rev Cancer 9:285–293

    Article  PubMed  CAS  Google Scholar 

  69. Yan HH, Pickup M, Pang Y, Gorska AE, Li Z, Chytil A, Geng Y, Gray JW, Moses HL, Yang L (2010) Gr-1+CD11b+ myeloid cells tip the balance of immune protection to tumor promotion in the premetastatic lung. Cancer Res 70:6139–6149

    Article  PubMed  CAS  Google Scholar 

  70. Kowanetz M, Wu X, Lee J, Tan M, Hagenbeek T, Qu X, Yu L, Ross J, Korsisaari N, Cao T, Bou-Reslan H, Kallop D, Weimer R, Ludlam MJ, Kaminker JS, Modrusan Z, van Bruggen N, Peale FV, Carano R, Meng YG, Ferrara N (2010) Granulocyte-colony stimulating factor promotes lung metastasis through mobilization of Ly6G+Ly6C+ granulocytes. Proc Natl Acad Sci U S A 107:21248–21255

    Article  PubMed  CAS  Google Scholar 

  71. Sceneay J, Chow MT, Chen A, Halse HM, Wong CS, Andrews DM, Sloan EK, Parker BS, Bowtell DD, Smyth MJ, Moller A (2012) Primary tumor hypoxia recruits CD11b+/Ly6Cmed/Ly6G+ immune suppressor cells and compromises NK cell cytotoxicity in the premetastatic niche. Cancer Res 72:3906–3911

    Google Scholar 

  72. Tazzyman S, Barry ST, Ashton S, Wood P, Blakey D, Lewis CE, Murdoch C (2011) 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

    Article  PubMed  CAS  Google Scholar 

  73. Wada Y, Yoshida K, Tsutani Y, Shigematsu H, Oeda M, Sanada Y, Suzuki T, Mizuiri H, Hamai Y, Tanabe K, Ukon K, Hihara J (2007) Neutrophil elastase induces cell proliferation and migration by the release of TGF-alpha, PDGF and VEGF in esophageal cell lines. Oncol Rep 17:161–167

    PubMed  CAS  Google Scholar 

  74. Giese A, Bjerkvig R, Berens ME, Westphal M (2003) Cost of migration: invasion of malignant gliomas and implications for treatment. J Clin Oncol 21:1624–1636

    Article  PubMed  CAS  Google Scholar 

  75. Jung A, Schrauder M, Oswald U, Knoll C, Sellberg P, Palmqvist R, Niedobitek G, Brabletz T, Kirchner T (2001) The invasion front of human colorectal adenocarcinomas shows co-localization of nuclear beta-catenin, cyclin D1, and p16INK4A and is a region of low proliferation. Am J Pathol 159:1613–1617

    Article  PubMed  CAS  Google Scholar 

  76. Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L, Worthen GS, Albelda SM (2009) Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell 16:183–194

    Article  PubMed  CAS  Google Scholar 

  77. Rotondo R, Barisione G, Mastracci L, Grossi F, Orengo AM, Costa R, Truini M, Fabbi M, Ferrini S, Barbieri O (2009) IL-8 induces exocytosis of arginase 1 by neutrophil polymorphonuclears in nonsmall cell lung cancer. Int J Cancer 125:887–893

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  79. Pickaver AH, Ratcliffe NA, Williams AE, Smith H (1972) Cytotoxic effects of peritoneal neutrophils on a syngeneic rat tumour. Nat New Biol 235:186–187

    PubMed  CAS  Google Scholar 

  80. Souto JC, Vila L, Bru A (2011) Polymorphonuclear neutrophils and cancer: intense and sustained neutrophilia as a treatment against solid tumors. Med Res Rev 31:311–363

    Article  PubMed  CAS  Google Scholar 

  81. van Egmond M (2008) Neutrophils in antibody-based immunotherapy of cancer. Expert Opin Biol Ther 8:83–94

    Article  PubMed  Google Scholar 

  82. Ottonello L, Epstein AL, Mancini M, Tortolina G, Dapino P, Dallegri F (2001) Chimaeric Lym-1 monoclonal antibody-mediated cytolysis by neutrophils from G-CSF-treated patients: stimulation by GM-CSF and role of Fc gamma-receptors. Br J Cancer 85:463–469

    Article  PubMed  CAS  Google Scholar 

  83. Cassatella MA, Flynn RM, Amezaga MA, Bazzoni F, Vicentini F, Trinchieri G (1990) Interferon gamma induces in human neutrophils and macrophages expression of the mRNA for the high affinity receptor for monomeric IgG (Fc gamma R-I or CD64). Biochem Biophys Res Commun 170:582–588

    Article  PubMed  CAS  Google Scholar 

  84. Valerius T, Repp R, de Wit TP, Berthold S, Platzer E, Kalden JR, Gramatzki M, van de Winkel JG (1993) Involvement of the high-affinity receptor for IgG (Fc gamma RI; CD64) in enhanced tumor cell cytotoxicity of neutrophils during granulocyte colony-stimulating factor therapy. Blood 82:931–939

    PubMed  CAS  Google Scholar 

  85. Su YB, Vickers AJ, Zelefsky MJ, Kraus DH, Shaha AR, Shah JP, Serio AM, Harrison LB, Bosl GJ, Pfister DG (2006) Double-blind, placebo-controlled, randomized trial of granulocyte-colony stimulating factor during postoperative radiotherapy for squamous head and neck cancer. Cancer J 12:182–188

    Article  PubMed  CAS  Google Scholar 

  86. Otten MA, Rudolph E, Dechant M, Tuk CW, Reijmers RM, Beelen RH, van de Winkel JG, van Egmond M (2005) Immature neutrophils mediate tumor cell killing via IgA but not IgG Fc receptors. J Immunol 174:5472–5480

    PubMed  CAS  Google Scholar 

  87. Huls G, Heijnen IA, Cuomo E, van der Linden J, Boel E, van de Winkel JG, Logtenberg T (1999) Antitumor immune effector mechanisms recruited by phage display-derived fully human IgG1 and IgA1 monoclonal antibodies. Cancer Res 59:5778–5784

    PubMed  CAS  Google Scholar 

  88. Theilgaard-Monch K, Jacobsen LC, Borup R, Rasmussen T, Bjerregaard MD, Nielsen FC, Cowland JB, Borregaard N (2005) The transcriptional program of terminal granulocytic differentiation. Blood 105:1785–1796

    Article  PubMed  CAS  Google Scholar 

  89. Dallegri F, Patrone F, Frumento G, Sacchetti C (1984) Antibody-dependent killing of tumor cells by polymorphonuclear leukocytes. Involvement of oxidative and nonoxidative mechanisms. J Natl Cancer Inst 73:331–339

    PubMed  CAS  Google Scholar 

  90. Dallegri F, Ottonello L, Ballestrero A, Dapino P, Ferrando F, Patrone F, Sacchetti C (1991) Tumor cell lysis by activated human neutrophils: analysis of neutrophil-delivered oxidative attack and role of leukocyte function-associated antigen 1. Inflammation 15:15–30

    Article  PubMed  CAS  Google Scholar 

  91. Clark RA, Klebanoff SJ (1975) Neutrophil-mediated tumor cell cytotoxicity: role of the peroxidase system. J Exp Med 141:1442–1447

    Article  PubMed  CAS  Google Scholar 

  92. Kushner BH, Cheung NK (1991) Clinically effective monoclonal antibody 3F8 mediates nonoxidative lysis of human neuroectodermal tumor cells by polymorphonuclear leukocytes. Cancer Res 51:4865–4870

    PubMed  CAS  Google Scholar 

  93. Grossman WJ, Ley TJ (2004) Granzymes A and B are not expressed in human neutrophils. Blood 104:906–907

    Article  PubMed  CAS  Google Scholar 

  94. Metkar SS, Froelich CJ (2004) Human neutrophils lack granzyme A, granzyme B, and perforin. Blood 104:905–906

    Article  PubMed  CAS  Google Scholar 

  95. Wagner C, Iking-Konert C, Denefleh B, Stegmaier S, Hug F, Hansch GM (2004) Granzyme B and perforin: constitutive expression in human polymorphonuclear neutrophils. Blood 103:1099–1104

    Article  PubMed  CAS  Google Scholar 

  96. Hubert P, Heitzmann A, Viel S, Nicolas A, Sastre-Garau X, Oppezzo P, Pritsch O, Osinaga E, Amigorena S (2011) Antibody-dependent cell cytotoxicity synapses form in mice during tumor-specific antibody immunotherapy. Cancer Res 71:5134–5143

    Article  PubMed  CAS  Google Scholar 

  97. Bakema JE, Ganzevles SH, Fluitsma DM, Schilham MW, Beelen RH, Valerius T, Lohse S, Glennie MJ, Medema JP, van Egmond M (2011) Targeting FcαRI on polymorphonuclear cells induces tumor cell killing through autophagy. J Immunol 187:726–732

    Article  PubMed  CAS  Google Scholar 

  98. Otten MA, Bakema JE, Tuk CW, Glennie MJ, Tutt AL, Beelen RH, van de Winkel JG, van Egmond M (2012) Enhanced FcαRI-mediated neutrophil migration towards tumour colonies in the presence of endothelial cells. Eur J Immunol 42(7):1815–1821

    Article  PubMed  CAS  Google Scholar 

  99. van Spriel AB, Leusen JH, van Egmond M, Dijkman HB, Assmann KJ, Mayadas TN, van de Winkel JG (2001) Mac-1 (CD11b/CD18) is essential for Fc receptor-mediated neutrophil cytotoxicity and immunologic synapse formation. Blood 97:2478–2486

    Article  PubMed  Google Scholar 

  100. Galluzzi L, Vacchelli E, Eggermont A, Fridman WH, Galon J, Sautes-Fridman C, Tartour E, Zitvogel L, Kroemer G (2012) Trial watch: experimental toll-like receptor agonists for cancer therapy. Oncoimmunology 1(5):699–716

    Article  PubMed  Google Scholar 

  101. Tadie JM, Bae HB, Banerjee S, Zmijewski JW, Abraham E (2012) Differential activation of RAGE by HMGB1 modulates neutrophil-associated NADPH oxidase activity and bacterial killing. Am J Physiol Cell Physiol 302:C249–C256

    Article  PubMed  CAS  Google Scholar 

  102. Kawai T, Akira S (2010) The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 11:373–384

    Article  PubMed  CAS  Google Scholar 

  103. Kersse K, Bertrand MJ, Lamkanfi M, Vandenabeele P (2011) NOD-like receptors and the innate immune system: coping with danger, damage and death. Cytokine Growth Factor Rev 22:257–276

    Article  PubMed  CAS  Google Scholar 

  104. Kandasamy M, Bay BH, Lee YK, Mahendran R (2011) Lactobacilli secreting a tumor antigen and IL15 activates neutrophils and dendritic cells and generates cytotoxic T lymphocytes against cancer cells. Cell Immunol 271:89–96

    Article  PubMed  CAS  Google Scholar 

  105. Suttmann H, Riemensberger J, Bentien G, Schmaltz D, Stockle M, Jocham D, Bohle A, Brandau S (2006) Neutrophil granulocytes are required for effective Bacillus Calmette–Guerin immunotherapy of bladder cancer and orchestrate local immune responses. Cancer Res 66:8250–8257

    Article  PubMed  CAS  Google Scholar 

  106. Brandau S, Suttmann H (2007) Thirty years of BCG immunotherapy for non-muscle invasive bladder cancer: a success story with room for improvement. Biomed Pharmacother 61:299–305

    Article  PubMed  CAS  Google Scholar 

  107. Cassatella MA (1999) Neutrophil-derived proteins: selling cytokines by the pound. Adv Immunol 73:369–509

    Article  PubMed  CAS  Google Scholar 

  108. Rosevear HM, Lightfoot AJ, O’Donnell MA, Griffith TS (2009) The role of neutrophils and TNF-related apoptosis-inducing ligand (TRAIL) in bacillus Calmette–Guerin (BCG) immunotherapy for urothelial carcinoma of the bladder. Cancer Metastasis Rev 28:345–353

    Article  PubMed  Google Scholar 

  109. Mittendorf EA, Alatrash G, Qiao N, Wu Y, Sukhumalchandra P, St John LS, Philips AV, Xiao H, Zhang M, Ruisaard K, Clise-Dwyer K, Lu S, Molldrem JJ (2012) Breast cancer cell uptake of the inflammatory mediator neutrophil elastase triggers an anticancer adaptive immune response. Cancer Res 72:3153–3162

    Article  PubMed  CAS  Google Scholar 

  110. Li B, Allendorf DJ, Hansen R, Marroquin J, Cramer DE, Harris CL, Yan J (2007) Combined yeast {beta}-glucan and antitumor monoclonal antibody therapy requires C5a-mediated neutrophil chemotaxis via regulation of decay-accelerating factor CD55. Cancer Res 67:7421–7430

    Article  PubMed  CAS  Google Scholar 

  111. Liu J, Gunn L, Hansen R, Yan J (2009) Combined yeast-derived beta-glucan with anti-tumor monoclonal antibody for cancer immunotherapy. Exp Mol Pathol 86:208–214

    Article  PubMed  CAS  Google Scholar 

  112. O’Connell J, O’Sullivan GC, Collins JK, Shanahan F (1996) The Fas counterattack: Fas-mediated T cell killing by colon cancer cells expressing Fas ligand. J Exp Med 184:1075–1082

    Article  PubMed  Google Scholar 

  113. Seino K, Kayagaki N, Okumura K, Yagita H (1997) Antitumor effect of locally produced CD95 ligand. Nat Med 3:165–170

    Article  PubMed  CAS  Google Scholar 

  114. Shimizu M, Fontana A, Takeda Y, Yagita H, Yoshimoto T, Matsuzawa A (1999) Induction of antitumor immunity with Fas/APO-1 ligand (CD95L)-transfected neuroblastoma neuro-2a cells. J Immunol 162:7350–7357

    PubMed  CAS  Google Scholar 

  115. Igney FH, Behrens CK, Krammer PH (2005) CD95L mediates tumor counterattack in vitro but induces neutrophil-independent tumor rejection in vivo. Int J Cancer 113:78–87

    Article  PubMed  CAS  Google Scholar 

  116. Dupont PJ, Warrens AN (2007) Fas ligand exerts its pro-inflammatory effects via neutrophil recruitment but not activation. Immunology 120:133–139

    Article  PubMed  CAS  Google Scholar 

  117. Hohlbaum AM, Gregory MS, Ju ST, Marshak-Rothstein A (2001) Fas ligand engagement of resident peritoneal macrophages in vivo induces apoptosis and the production of neutrophil chemotactic factors. J Immunol 167:6217–6224

    PubMed  CAS  Google Scholar 

  118. Wada A, Tada Y, Kawamura K, Takiguchi Y, Tatsumi K, Kuriyama T, Takenouchi T, Wang J, Tagawa M (2007) The effects of FasL on inflammation and tumor survival are dependent on its expression levels. Cancer Gene Ther 14:262–267

    Article  PubMed  CAS  Google Scholar 

  119. Musiani P, Allione A, Modica A, Lollini PL, Giovarelli M, Cavallo F, Belardelli F, Forni G, Modesti A (1996) Role of neutrophils and lymphocytes in inhibition of a mouse mammary adenocarcinoma engineered to release IL-2, IL-4, IL-7, IL-10, IFN-alpha, IFN-gamma, and TNF-alpha. Lab Invest 74:146–157

    PubMed  CAS  Google Scholar 

  120. Stoppacciaro A, Melani C, Parenza M, Mastracchio A, Bassi C, Baroni C, Parmiani G, Colombo MP (1993) Regression of an established tumor genetically modified to release granulocyte colony-stimulating factor requires granulocyte-T cell cooperation and T cell-produced interferon gamma. J Exp Med 178:151–161

    Article  PubMed  CAS  Google Scholar 

  121. Stoppacciaro A, Forni G, Colombo MP (1994) Different tumours, transduced with different cytokine genes as G-CSF and IL-2, show inhibition of tumour take through neutrophil activation but differ in T cell functions. Folia Biol (Praha) 40:89–99

    CAS  Google Scholar 

  122. Fridlender ZG, Albelda SM (2012) Tumor-associated neutrophils: friend or foe? Carcinogenesis 33:949–955

    Article  PubMed  CAS  Google Scholar 

  123. Scapini P, Nesi L, Morini M, Tanghetti E, Belleri M, Noonan D, Presta M, Albini A, Cassatella MA (2002) Generation of biologically active angiostatin kringle 1-3 by activated human neutrophils. J Immunol 168:5798–5804

    PubMed  CAS  Google Scholar 

  124. Granot Z, Henke E, Comen EA, King TA, Norton L, Benezra R (2011) Tumor entrained neutrophils inhibit seeding in the premetastatic lung. Cancer Cell 20:300–314

    Article  PubMed  CAS  Google Scholar 

  125. Lopez-Lago MA, Posner S, Thodima VJ, Molina AM, Motzer RJ, Chaganti RS (2012) Neutrophil chemokines secreted by tumor cells mount a lung antimetastatic response during renal cell carcinoma progression. Oncogene. doi:10.1038/onc.2012.201 [Epub ahead of print]

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Acknowledgments

The authors thank Katrin Moses for her help during preparation of this manuscript. Work presented in this manuscript was in part supported by grants from the Deutsche Forschungsgemeinschaft (to S.B.) and the Krebsgesellschaft NRW e.V (to S.B. and S.L.)

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Correspondence to Sven Brandau.

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This article is a contribution to the special issue on Inflammation and Cancer - Guest Editor: Takuji Tanaka

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Brandau, S., Dumitru, C.A. & Lang, S. Protumor and antitumor functions of neutrophil granulocytes. Semin Immunopathol 35, 163–176 (2013). https://doi.org/10.1007/s00281-012-0344-6

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