Neutrophils in the tumor microenvironment: trying to heal the wound that cannot heal

Immunological Reviews

Volumn 273, Issue 1, 2016, Pages 329-343

  Singel, Kelly L ^a   Segal, Brahm H ^a,b  

^a ROSWELL PARK CANCER INSTITUTE   (United States)

^b UNIVERSITY AT BUFFALO   (United States)

Author keywords

cancer; inflammation; injury; neutrophils; wound repair

Indexed keywords

COLONY STIMULATING FACTOR; CYTOKINE; GROWTH FACTOR;

ANGIOGENESIS; CANCER CHEMOTHERAPY; CANCER SURGERY; CARCINOGENESIS; CELL HETEROGENEITY; CELLULAR IMMUNITY; EXTRACELLULAR TRAP; HUMAN; IMMUNE RESPONSE; INFLAMMATION; LEUKOCYTE ACTIVATION; LEUKOCYTOSIS; METASTASIS; MYELOPOIESIS; NEUTROPHIL; NONHUMAN; OVARY CANCER; PRIORITY JOURNAL; REVIEW; STROMA; T LYMPHOCYTE; THROMBOCYTE; THROMBOSIS; TUMOR CELL; TUMOR GROWTH; TUMOR IMMUNITY; TUMOR MICROENVIRONMENT; WOUND HEALING; WOUND HEALING IMPAIRMENT;

EID: 84983489028     PISSN: 01052896     EISSN: 1600065X     Source Type: Journal    
DOI: 10.1111/imr.12459     Document Type: Review

References (200)

1. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 2001;357:539–545.
2. Pikarsky E, Porat RM, Stein I, et al. NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature. 2004;431:461–466.
3. DiDonato JA, Mercurio F, Karin M. NF-kappaB and the link between inflammation and cancer. Immunol Rev. 2012;246:379–400.
4. Palucka AK, Coussens LM. The basis of oncoimmunology. Cell. 2016;164:1233–1247.
5. Kryczek I, Zou L, Rodriguez P, et al. B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma. J Exp Med. 2006;203:871–881.
6. Rodriguez D, Silvera R, Carrio R, et al. Tumor microenvironment profoundly modifies functional status of macrophages: peritoneal and tumor-associated macrophages are two very different subpopulations. Cell Immunol. 2013;283:51–60.
7. Torroella-Kouri M, Silvera R, Rodriguez D, et al. Identification of a subpopulation of macrophages in mammary tumor-bearing mice that are neither M1 nor M2 and are less differentiated. Cancer Res. 2009;69:4800–4809.
8. Khan AN, Kolomeyevskaya N, Singel KL, et al. Targeting myeloid cells in the tumor microenvironment enhances vaccine efficacy in murine epithelial ovarian cancer. Oncotarget. 2015;6:11310–11326.
9. Dangaj D, Lanitis E, Zhao A, et al. Novel recombinant human b7-h4 antibodies overcome tumoral immune escape to potentiate T-cell antitumor responses. Cancer Res. 2013;73:4820–4829.
10. Pekarek LA, Starr BA, Toledano AY, Schreiber H. Inhibition of tumor growth by elimination of granulocytes. J Exp Med. 1995;181:435–440.
11. Stark MA, Huo Y, Burcin TL, Morris MA, Olson TS, Ley K. Phagocytosis of apoptotic neutrophils regulates granulopoiesis via IL-23 and IL-17. Immunity. 2005;22:285–294.
12. Dvorak HF. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med. 1986;315:1650–1659.
13. Donskov F. Immunomonitoring and prognostic relevance of neutrophils in clinical trials. Semin Cancer Biol. 2013;23:200–207.
14. Absenger G, Szkandera J, Pichler M, et al. A derived neutrophil to lymphocyte ratio predicts clinical outcome in stage II and III colon cancer patients. Br J Cancer. 2013;109:395–400.
15. Yao Y, Yuan D, Liu H, Gu X, Song Y. Pretreatment neutrophil to lymphocyte ratio is associated with response to therapy and prognosis of advanced non-small cell lung cancer patients treated with first-line platinum-based chemotherapy. Cancer Immunol Immunother. 2013;62:471–479.
16. Jafri SH, Shi R, Mills G. Advance lung cancer inflammation index (ALI) at diagnosis is a prognostic marker in patients with metastatic non-small cell lung cancer (NSCLC): a retrospective review. BMC Cancer. 2013;13:158.
17. Motomura T, Shirabe K, Mano Y, et al. Neutrophil-lymphocyte ratio reflects hepatocellular carcinoma recurrence after liver transplantation via inflammatory microenvironment. J Hepatol. 2013;58:58–64.
18. Zhou SL, Dai Z, Zhou ZJ, et al. Overexpression of CXCL5 mediates neutrophil infiltration and indicates poor prognosis for hepatocellular carcinoma. Hepatology. 2012;56:2242–2254.
19. Wang GY, Yang Y, Li H, et al. A scoring model based on neutrophil to lymphocyte ratio predicts recurrence of HBV-associated hepatocellular carcinoma after liver transplantation. PLoS ONE. 2011;6:e25295.
20. Dumitru CA, Bankfalvi A, Gu X, Zeidler R, Brandau S, Lang S. AHNAK and inflammatory markers predict poor survival in laryngeal carcinoma. PLoS ONE. 2013;8:e56420.
21. Banerjee S, Rustin G, Paul J, et al. A multicenter, randomized trial of flat dosing versus intrapatient dose escalation of single-agent carboplatin as first-line chemotherapy for advanced ovarian cancer: an SGCTG (SCOTROC 4) and ANZGOG study on behalf of GCIG. Ann Oncol. 2013;24:679–687.
22. Cho H, Hur HW, Kim SW, et al. Pre-treatment neutrophil to lymphocyte ratio is elevated in epithelial ovarian cancer and predicts survival after treatment. Cancer Immunol Immunother. 2009;58:15–23.
23. Wu WC, Sun HW, Chen HT, et al. Circulating hematopoietic stem and progenitor cells are myeloid-biased in cancer patients. Proc Natl Acad Sci USA. 2014;111:4221–4226.
24. Casbon AJ, Reynaud D, Park C, et al. Invasive breast cancer reprograms early myeloid differentiation in the bone marrow to generate immunosuppressive neutrophils. Proc Natl Acad Sci USA. 2015;112:E566–E575.
25. Strauss L, Sangaletti S, Consonni FM, et al. RORC1 regulates tumor-promoting “emergency” granulo-monocytopoiesis. Cancer Cell. 2015;28:253–269.
26. van Kempen LC, Coussens LM. MMP9 potentiates pulmonary metastasis formation. Cancer Cell. 2002;2:251–252.
27. Kaplan RN, Riba RD, Zacharoulis S, et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature. 2005;438:820–827.
28. Hiratsuka S, Watanabe A, Aburatani H, Maru Y. Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis. Nat Cell Biol. 2006;8:1369–1375.
29. Shojaei F, Wu X, Zhong C, et al. Bv8 regulates myeloid-cell-dependent tumour angiogenesis. Nature. 2007;450:825–831.
30. Shojaei F, Singh M, Thompson JD, Ferrara N. Role of Bv8 in neutrophil-dependent angiogenesis in a transgenic model of cancer progression. Proc Natl Acad Sci USA. 2008;105:2640–2645.
31. Kowanetz M, Wu X, Lee J, et al. Granulocyte-colony stimulating factor promotes lung metastasis through mobilization of Ly6G+Ly6C+ granulocytes. Proc Natl Acad Sci USA. 2010;107:21248–21255.
32. Wculek SK, Malanchi I. Neutrophils support lung colonization of metastasis-initiating breast cancer cells. Nature. 2015;528:413–417.
33. Granot Z, Henke E, Comen EA, King TA, Norton L, Benezra R. Tumor entrained neutrophils inhibit seeding in the premetastatic lung. Cancer Cell. 2011;20:300–314.
34. Blaisdell A, Crequer A, Columbus D, et al. Neutrophils oppose uterine epithelial carcinogenesis via debridement of hypoxic tumor cells. Cancer Cell. 2015;28:785–799.
35. Fridlender ZG, Albelda SM. Tumor-associated neutrophils: friend or foe? Carcinogenesis. 2012;33:949–955.
36. Gabrilovich DI, Ostrand-Rosenberg S, Bronte V. Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol. 2012;12:253–268.
37. Janols H, Bergenfelz C, Allaoui R, et al. A high frequency of MDSCs in sepsis patients, with the granulocytic subtype dominating in gram-positive cases. J Leukoc Biol. 2014;96:685–693.
38. Darcy CJ, Minigo G, Piera KA, et al. Neutrophils with myeloid derived suppressor function deplete arginine and constrain T cell function in septic shock patients. Crit Care. 2014;18:R163.
39. Solito S, Marigo I, Pinton L, Damuzzo V, Mandruzzato S, Bronte V. Myeloid-derived suppressor cell heterogeneity in human cancers. Ann N Y Acad Sci. 2014;1319:47–65.
40. Sinha P, Parker KH, Horn L, Ostrand-Rosenberg S. Tumor-induced myeloid-derived suppressor cell function is independent of IFN-γ and IL-4Rα. Eur J Immunol. 2012;42:2052–2059.
41. Youn JI, Nagaraj S, Collazo M, Gabrilovich DI. Subsets of myeloid-derived suppressor cells in tumor-bearing mice. J Immunol. 2008;181:5791–5802.
42. Mandruzzato S, Brandau S, Britten CM, et al. Toward harmonized phenotyping of human myeloid-derived suppressor cells by flow cytometry: results from an interim study. Cancer Immunol Immunother. 2016;65:161–169.
43. Solito S, Falisi E, Diaz-Montero CM, et al. A human promyelocytic-like population is responsible for the immune suppression mediated by myeloid-derived suppressor cells. Blood. 2011;118:2254–2265.
44. Giles AJ, Reid CM, Evans JD, et al. Activation of hematopoietic stem/progenitor cells promotes immunosuppression within the pre-metastatic niche. Cancer Res. 2016;76:1335–1347.
45. Marigo I, Bosio E, Solito S, et al. Tumor-induced tolerance and immune suppression depend on the C/EBPbeta transcription factor. Immunity. 2010;32:790–802.
46. Farren MR, Carlson LM, Netherby CS, et al. Tumor-induced STAT3 signaling in myeloid cells impairs dendritic cell generation by decreasing PKCbetaII abundance. Sci Signal. 2014;7:ra16.
47. Waight JD, Netherby CS, Hensen ML, et al. Myeloid-derived suppressor cell development is regulated by a STAT/IRF-8 axis. J Clin Invest. 2013;123:4464–4478.
48. Vasquez-Dunddel D, Pan F, Zeng Q, et al. STAT3 regulates arginase-I in myeloid-derived suppressor cells from cancer patients. J Clin Invest. 2013;123:1580–1589.
49. Mace TA, Ameen Z, Collins A, et al. Pancreatic cancer-associated stellate cells promote differentiation of myeloid-derived suppressor cells in a STAT3-dependent manner. Cancer Res. 2013;73:3007–3018.
50. Corzo CA, Cotter MJ, Cheng P, et al. Mechanism regulating reactive oxygen species in tumor-induced myeloid-derived suppressor cells. J Immunol. 2009;182:5693–5701.
51. Godoy HE, Khan AN, Vethanayagam RR, et al. Myeloid-derived suppressor cells modulate immune responses independently of NADPH oxidase in the ovarian tumor microenvironment in mice. PLoS ONE. 2013;8:e69631.
52. Zarbock A, Singbartl K, Ley K. Complete reversal of acid-induced acute lung injury by blocking of platelet-neutrophil aggregation. J Clin Invest. 2006;116:3211–3219.
53. Grommes J, Alard JE, Drechsler M, et al. Disruption of platelet-derived chemokine heteromers prevents neutrophil extravasation in acute lung injury. Am J Respir Crit Care Med. 2012;185:628–636.
54. Sreeramkumar V, Adrover JM, Ballesteros I, et al. Neutrophils scan for activated platelets to initiate inflammation. Science. 2014;346:1234–1238.
55. Boilard E, Nigrovic PA, Larabee K, et al. Platelets amplify inflammation in arthritis via collagen-dependent microparticle production. Science. 2010;327:580–583.
56. Duchez AC, Boudreau LH, Naika GS, et al. Platelet microparticles are internalized in neutrophils via the concerted activity of 12-lipoxygenase and secreted phospholipase A2-IIA. Proc Natl Acad Sci USA. 2015;112:E3564–E3573.
57. Boudreau LH, Duchez AC, Cloutier N, et al. Platelets release mitochondria serving as substrate for bactericidal group IIA-secreted phospholipase A2 to promote inflammation. Blood. 2014;124:2173–2183.
58. Lammermann T, Afonso PV, Angermann BR, et al. Neutrophil swarms require LTB4 and integrins at sites of cell death in vivo. Nature. 2013;498:371–375.
59. Herron MJ, Nelson CM, Larson J, Snapp KR, Kansas GS, Goodman JL. Intracellular parasitism by the human granulocytic ehrlichiosis bacterium through the P-selectin ligand, PSGL-1. Science. 2000;288:1653–1656.
60. Lichtenstein A, Kahle J. Anti-tumor effect of inflammatory neutrophils: characteristics of in vivo generation and in vitro tumor cell lysis. Int J Cancer. 1985;35:121–127.
61. Otten MA, Rudolph E, Dechant M, et al. Immature neutrophils mediate tumor cell killing via IgA but not IgG Fc receptors. J Immunol. 2005;174:5472–5480.
62. Stockmeyer B, Beyer T, Neuhuber W, et al. Polymorphonuclear granulocytes induce antibody-dependent apoptosis in human breast cancer cells. J Immunol. 2003;171:5124–5129.
63. Mittendorf EA, Alatrash G, Qiao N, et al. Breast cancer cell uptake of the inflammatory mediator neutrophil elastase triggers an anticancer adaptive immune response. Cancer Res. 2012;72:3153–3162.
64. Harrison JE, Schultz J. Studies on the chlorinating activity of myeloperoxidase. J Biol Chem. 1976;251:1371–1374.
65. Albrich JM, McCarthy CA, Hurst JK. Biological reactivity of hypochlorous acid: implications for microbicidal mechanisms of leukocyte myeloperoxidase. Proc Natl Acad Sci USA. 1981;78:210–214.
66. Weiss SJ, Klein R, Slivka A, Wei M. Chlorination of taurine by human neutrophils. Evidence for hypochlorous acid generation. J Clin Invest. 1982;70:598–607.
67. Clark RA, Klebanoff SJ. Neutrophil-mediated tumor cell cytotoxicity: role of the peroxidase system. J Exp Med. 1975;141:1442–1447.
68. Clark RA, Klebanoff SJ. Role of the myeloperoxidase-H2O2-halide system in concanavalin A-induced tumor cell killing by human neutrophils. J Immunol. 1979;122:2605–2610.
69. Clark RA, Klebanoff SJ, Einstein AB, Fefer A. Peroxidase-H2O2-halide system: cytotoxic effect on mammalian tumor cells. Blood. 1975;45:161–170.
70. Clark RA, Szot S. The myeloperoxidase-hydrogen peroxide-halide system as effector of neutrophil-mediated tumor cell cytotoxicity. J Immunol. 1981;126:1295–1301.
71. Reeves EP, Lu H, Jacobs HL, et al. Killing activity of neutrophils is mediated through activation of proteases by K+ flux. Nature. 2002;416:291–297.
72. Clark RA, Olsson I, Klebanoff SJ. Cytotoxicity for tumor cells of cationic proteins from human neutrophil granules. J Cell Biol. 1976;70:719–723.
73. El-Hag A, Clark RA. Down-regulation of human natural killer activity against tumors by the neutrophil myeloperoxidase system and hydrogen peroxide. J Immunol. 1984;133:3291–3297.
74. el-Hag A, Clark RA. Immunosuppression by activated human neutrophils. Dependence on the myeloperoxidase system. J Immunol. 1987;139:2406–2413.
75. el-Hag A, Lipsky PE, Bennett M, Clark RA. Immunomodulation by neutrophil myeloperoxidase and hydrogen peroxide: differential susceptibility of human lymphocyte functions. J Immunol. 1986;136:3420–3426.
76. Bianchi M, Hakkim A, Brinkmann V, et al. Restoration of NET formation by gene therapy in CGD controls aspergillosis. Blood. 2009;114:2619–2622.
77. Fuchs TA, Abed U, Goosmann C, et al. Novel cell death program leads to neutrophil extracellular traps. J Cell Biol. 2007;176:231–241.
78. Brinkmann V, Reichard U, Goosmann C, et al. Neutrophil extracellular traps kill bacteria. Science. 2004;303:1532–1535.
79. Rohm M, Grimm MJ, D'Auria AC, Almyroudis NG, Segal BH, Urban CF. NADPH oxidase promotes neutrophil extracellular trap formation in pulmonary aspergillosis. Infect Immun. 2014;82:1766–1777.
80. Itagaki K, Kaczmarek E, Lee YT, et al. Mitochondrial DNA released by trauma induces neutrophil extracellular traps. PLoS ONE. 2015;10:e0120549.
81. Arai Y, Nishinaka Y, Arai T, et al. Uric acid induces NADPH oxidase-independent neutrophil extracellular trap formation. Biochem Biophys Res Commun. 2014;443:556–561.
82. Caudrillier A, Kessenbrock K, Gilliss BM, et al. Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury. J Clin Invest. 2012;122:2661–2671.
83. Thomas GM, Carbo C, Curtis BR, et al. Extracellular DNA traps are associated with the pathogenesis of TRALI in humans and mice. Blood. 2012;119:6335–6343.
84. Douda DN, Khan MA, Grasemann H, Palaniyar N. SK3 channel and mitochondrial ROS mediate NADPH oxidase-independent NETosis induced by calcium influx. Proc Natl Acad Sci USA. 2015;112:2817–2822.
85. Narasaraju T, Yang E, Samy RP, et al. Excessive neutrophils and neutrophil extracellular traps contribute to acute lung injury of influenza pneumonitis. Am J Pathol. 2011;179:199–210.
86. Rossaint J, Herter JM, Van Aken H, et al. Synchronized integrin engagement and chemokine activation is crucial in neutrophil extracellular trap mediated sterile inflammation. Blood. 2014;123:2573–2584.
87. Semeraro F, Ammollo CT, Morrissey JH, et al. Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4. Blood. 2011;118:1952–1961.
88. Fuchs TA, Brill A, Duerschmied D, et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci USA. 2010;107:15880–15885.
89. Martinod K, Wagner DD. Thrombosis: tangled up in NETs. Blood. 2014;123:2768–2776.
90. Demers M, Krause DS, Schatzberg D, et al. Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis. Proc Natl Acad Sci USA. 2012;109:13076–13081.
91. Brill A, Fuchs TA, Savchenko AS, et al. Neutrophil extracellular traps promote deep vein thrombosis in mice. J Thromb Haemost. 2012;10:136–144.
92. von Bruhl ML, Stark K, Steinhart A, et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med. 2012;209:819–835.
93. Stakos DA, Kambas K, Konstantinidis T, et al. Expression of functional tissue factor by neutrophil extracellular traps in culprit artery of acute myocardial infarction. Eur Heart J. 2015;36:1405–1414.
94. Martinod K, Demers M, Fuchs TA, et al. Neutrophil histone modification by peptidylarginine deiminase 4 is critical for deep vein thrombosis in mice. Proc Natl Acad Sci USA. 2013;110:8674–8679.
95. Clark SR, Ma AC, Tavener SA, et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med. 2007;13:463–469.
96. Etulain J, Martinod K, Wong SL, Cifuni SM, Schattner M, Wagner DD. P-selectin promotes neutrophil extracellular trap formation in mice. Blood. 2015;126:242–246.
97. Thalin C, Demers M, Blomgren B, et al. NETosis promotes cancer-associated arterial microthrombosis presenting as ischemic stroke with troponin elevation. Thromb Res. 2016;139:56–64.
98. Cools-Lartigue J, Spicer J, McDonald B, et al. Neutrophil extracellular traps sequester circulating tumor cells and promote metastasis. J Clin Invest. 2013;123:3446–3458.
99. Guglietta S, Chiavelli A, Zagato E, et al. Coagulation induced by C3aR-dependent NETosis drives protumorigenic neutrophils during small intestinal tumorigenesis. Nat Commun. 2016;7:11037.
100. Tohme S, Yazdani HO, Al-Khafaji AB, et al. Neutrophil extracellular traps promote the development and progression of liver metastases after surgical stress. Cancer Res. 2016;76:1367–1380.
101. Berger-Achituv S, Brinkmann V, Abed UA, et al. A proposed role for neutrophil extracellular traps in cancer immunoediting. Front Immunol. 2013;4:48.
102. Boone BA, Orlichenko L, Schapiro NE, et al. The receptor for advanced glycation end products (RAGE) enhances autophagy and neutrophil extracellular traps in pancreatic cancer. Cancer Gene Ther. 2015;22:326–334.
103. Alfaro C, Teijeira A, Onate C, et al. Tumor-produced interleukin-8 attracts human myeloid-derived suppressor cells and elicits extrusion of neutrophil extracellular traps (NETs). Clin Cancer Res. 2016; Epub ahead of print.
104. Palumbo JS, Kombrinck KW, Drew AF, et al. Fibrinogen is an important determinant of the metastatic potential of circulating tumor cells. Blood. 2000;96:3302–3309.
105. Cedervall J, Zhang Y, Huang H, et al. Neutrophil extracellular traps accumulate in peripheral blood vessels and compromise organ function in tumor-bearing animals. Cancer Res. 2015;75:2653–2662.
106. Stone RL, Nick AM, McNeish IA, et al. Paraneoplastic thrombocytosis in ovarian cancer. N Engl J Med. 2012;366:610–618.
107. Sharma D, Brummel-Ziedins KE, Bouchard BA, Holmes CE. Platelets in tumor progression: a host factor that offers multiple potential targets in the treatment of cancer. J Cell Physiol. 2014;229:1005–1015.
108. Gotzmann J, Fischer AN, Zojer M, et al. A crucial function of PDGF in TGF-beta-mediated cancer progression of hepatocytes. Oncogene. 2006;25:3170–3185.
109. Jechlinger M, Sommer A, Moriggl R, et al. Autocrine PDGFR signaling promotes mammary cancer metastasis. J Clin Invest. 2006;116:1561–1570.
110. Labelle M, Begum S, Hynes RO. Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer Cell. 2011;20:576–590.
111. Ishida Y, Kondo T, Takayasu T, Iwakura Y, Mukaida N. The essential involvement of cross-talk between IFN-gamma and TGF-beta in the skin wound-healing process. J Immunol. 2004;172:1848–1855.
112. Reynolds LE, Conti FJ, Lucas M, et al. Accelerated re-epithelialization in beta3-integrin-deficient- mice is associated with enhanced TGF-beta1 signaling. Nat Med. 2005;11:167–174.
113. Mangan PR, Harrington LE, O'Quinn DB, et al. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature. 2006;441:231–234.
114. Mucida D, Park Y, Kim G, et al. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science. 2007;317:256–260.
115. Terabe M, Matsui S, Park JM, et al. Transforming growth factor-beta production and myeloid cells are an effector mechanism through which CD1d-restricted T cells block cytotoxic T lymphocyte-mediated tumor immunosurveillance: abrogation prevents tumor recurrence. J Exp Med. 2003;198:1741–1752.
116. Fridlender ZG, Sun J, Kim S, et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell. 2009;16:183–194.
117. Sagiv JY, Michaeli J, Assi S, et al. Phenotypic diversity and plasticity in circulating neutrophil subpopulations in cancer. Cell Rep. 2015;10:562–573.
118. Labelle M, Begum S, Hynes RO. Platelets guide the formation of early metastatic niches. Proc Natl Acad Sci USA. 2014;111:E3053–E3061.
119. Hampton HR, Bailey J, Tomura M, Brink R, Chtanova T. Microbe-dependent lymphatic migration of neutrophils modulates lymphocyte proliferation in lymph nodes. Nat Commun. 2015;6:7139.
120. Hampton HR, Chtanova T. The lymph node neutrophil. Semin Immunol. 2016;28:129–136.
121. Lim K, Hyun YM, Lambert-Emo K, et al. Neutrophil trails guide influenza-specific CD8(+) T cells in the airways. Science. 2015;349:aaa4352.
122. Pillay J, Kamp VM, van Hoffen E, et al. A subset of neutrophils in human systemic inflammation inhibits T cell responses through Mac-1. J Clin Invest. 2012;122:327–336.
123. Yang CW, Unanue ER. Neutrophils control the magnitude and spread of the immune response in a thromboxane A2-mediated process. J Exp Med. 2013;210:375–387.
124. Langowski JL, Zhang X, Wu L, et al. IL-23 promotes tumour incidence and growth. Nature. 2006;442:461–465.
125. Coussens LM, Tinkle CL, Hanahan D, Werb Z. MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis. Cell. 2000;103:481–490.
126. 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. 2006;103:12493–12498.
127. Jablonska J, Leschner S, Westphal K, Lienenklaus S, Weiss S. Neutrophils responsive to endogenous IFN-beta regulate tumor angiogenesis and growth in a mouse tumor model. J Clin Invest. 2010;120:1151–1164.
128. Chung AS, Wu X, Zhuang G, et al. An interleukin-17-mediated paracrine network promotes tumor resistance to anti-angiogenic therapy. Nat Med. 2013;19:1114–1123.
129. Langowski JL, Kastelein RA, Oft M. Swords into plowshares: IL-23 repurposes tumor immune surveillance. Trends Immunol. 2007;28:207–212.
130. Grivennikov SI, Wang K, Mucida D, et al. Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. Nature. 2012;491:254–258.
131. Tosolini M, Kirilovsky A, Mlecnik B, et al. Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer. Cancer Res. 2011;71:1263–1271.
132. Coffelt SB, Kersten K, Doornebal CW, et al. IL-17-producing gammadelta T cells and neutrophils conspire to promote breast cancer metastasis. Nature. 2015;522:345–348.
133. Koyama S, Akbay EA, Li YY, et al. STK11/LKB1 deficiency promotes neutrophil recruitment and proinflammatory cytokine production to suppress T-cell activity in the lung tumor microenvironment. Cancer Res. 2016;76:999–1008.
134. Zhou SL, Zhou ZJ, Hu ZQ, et al. Tumor-associated neutrophils recruit macrophages and t-regulatory cells to promote progression of hepatocellular carcinoma and resistance to sorafenib. Gastroenterology. 2016;150:1646–1658.
135. Jacobsen LC, Theilgaard-Monch K, Christensen EI, Borregaard N. Arginase 1 is expressed in myelocytes/metamyelocytes and localized in gelatinase granules of human neutrophils. Blood. 2007;109:3084–3087.
136. Rotondo R, Barisione G, Mastracci L, et al. IL-8 induces exocytosis of arginase 1 by neutrophil polymorphonuclears in nonsmall cell lung cancer. Int J Cancer. 2009;125:887–893.
137. Rotondo R, Bertolotto M, Barisione G, et al. Exocytosis of azurophil and arginase 1-containing granules by activated polymorphonuclear neutrophils is required to inhibit T lymphocyte proliferation. J Leukoc Biol. 2011;89:721–727.
138. Rodriguez PC, Ernstoff MS, Hernandez C, et al. Arginase I-producing myeloid-derived suppressor cells in renal cell carcinoma are a subpopulation of activated granulocytes. Cancer Res. 2009;69:1553–1560.
139. Geissmann F, Manz MG, Jung S, Sieweke MH, Merad M, Ley K. Development of monocytes, macrophages, and dendritic cells. Science. 2010;327:656–661.
140. Gomez Perdiguero E, Klapproth K, Schulz C, et al. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature. 2015;518:547–551.
141. Brown CC, Malech HL, Jacobson RJ, et al. Unique human neutrophil populations are defined by monoclonal antibody ED12F8C10. Cell Immunol. 1991;132:102–114.
142. Gallin JI, Jacobson RJ, Seligmann B, et al. A marker of neutrophil heterogeneity reveals two forms of chronic myelogenous leukemia. Trans Assoc Am Physicians. 1985;98:166–170.
143. Seligmann B, Chused TM, Gallin JI. Human neutrophil heterogeneity identified using flow microfluorometry to monitor membrane potential. J Clin Invest. 1981;68:1125–1131.
144. Seligmann B, Malech HL, Melnick DA, Gallin JI. An antibody to a subpopulation of neutrophils demonstrates antigenic heterogeneity which correlates with response heterogeneity. Trans Assoc Am Physicians. 1984;97:319–324.
145. Seligmann B, Malech HL, Melnick DA, Gallin JI. An antibody binding to human neutrophils demonstrates antigenic heterogeneity detected early in myeloid maturation which correlates with functional heterogeneity of mature neutrophils. J Immunol. 1985;135:2647–2653.
146. Gallin JI. Human neutrophil heterogeneity exists, but is it meaningful? Blood. 1984;63:977–983.
147. Mishalian I, Bayuh R, Levy L, Zolotarov L, Michaeli J, Fridlender ZG. Tumor-associated neutrophils (TAN) develop pro-tumorigenic properties during tumor progression. Cancer Immunol Immunother. 2013;62:1745–1756.
148. Tazawa H, Okada F, Kobayashi T, 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. 2003;163:2221–2232.
149. Scapini P, Lapinet-Vera JA, Gasperini S, Calzetti F, Bazzoni F, Cassatella MA. The neutrophil as a cellular source of chemokines. Immunol Rev. 2000;177:195–203.
150. Beauvillain C, Delneste Y, Scotet M, et al. Neutrophils efficiently cross-prime naive T cells in vivo. Blood. 2007;110:2965–2973.
151. + T cells. Immunity. 2012;37:917–929.
152. Geng S, Matsushima H, Okamoto T, et al. Emergence, origin, and function of neutrophil-dendritic cell hybrids in experimentally induced inflammatory lesions in mice. Blood. 2013;121:1690–1700.
153. Matsushima H, Geng S, Lu R, et al. Neutrophil differentiation into a unique hybrid population exhibiting dual phenotype and functionality of neutrophils and dendritic cells. Blood. 2013;121:1677–1689.
154. Winter WE 3rd, Maxwell GL, Tian C, et al. Prognostic factors for stage III epithelial ovarian cancer: a Gynecologic Oncology Group Study. J Clin Oncol. 2007;25:3621–3627.
155. Zhang L, Conejo-Garcia JR, Katsaros D, et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med. 2003;348:203–213.
156. +/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci USA. 2005;102:18538–18543.
157. Curiel TJ, Coukos G, Zou L, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 2004;10:942–949.
158. Simpson-Abelson MR, Loyall JL, Lehman HK, et al. Human ovarian tumor ascites fluids rapidly and reversibly inhibit T cell receptor-induced NF-kappaB and NFAT signaling in tumor-associated T cells. Cancer Immun. 2013;13:14.
159. Obermajer N, Wong JL, Edwards RP, et al. Induction and stability of human Th17 cells require endogenous NOS2 and cGMP-dependent NO signaling. J Exp Med. 2013;210:1433–1445.
160. Mhawech-Fauceglia P, Wang D, Ali L, et al. Intraepithelial T cells and tumor-associated macrophages in ovarian cancer patients. Cancer Immun. 2013;13:1.
161. Obermajer N, Muthuswamy R, Odunsi K, Edwards RP, Kalinski P. PGE(2)-induced CXCL12 production and CXCR4 expression controls the accumulation of human MDSCs in ovarian cancer environment. Cancer Res. 2011;71:7463–7470.
162. Lo CW, Chen MW, Hsiao M, et al. IL-6 trans-signaling in formation and progression of malignant ascites in ovarian cancer. Cancer Res. 2011;71:424–434.
163. Lane D, Matte I, Rancourt C, Piche A. Prognostic significance of IL-6 and IL-8 ascites levels in ovarian cancer patients. BMC Cancer. 2011;11:210.
164. Giuntoli RL 2nd, Webb TJ, Zoso A, et al. Ovarian cancer-associated ascites demonstrates altered immune environment: implications for antitumor immunity. Anticancer Res. 2009;29:2875–2884.
165. Obermajer N, Muthuswamy R, Odunsi KO, Edwards R, Kalinski P. PGE2-dependent CXCL12 production and CXCR4 expression control the accumulation of human MDSCs in ovarian cancer environment. Cancer Res. 2011;71:7463–7470.
166. Kryczek I, Wei S, Zhu G, et al. Relationship between B7-H4, regulatory T cells, and patient outcome in human ovarian carcinoma. Cancer Res. 2007;67:8900–8905.
167. Naldini A, Morena E, Belotti D, Carraro F, Allavena P, Giavazzi R. Identification of thrombin-like activity in ovarian cancer associated ascites and modulation of multiple cytokine networks. Thromb Haemost. 2011;106:705–711.
168. Wilhelm O, Hafter R, Henschen A, Schmitt M, Graeff H. Role of plasmin in the degradation of the stroma-derived fibrin in human ovarian carcinoma. Blood. 1990;75:1673–1678.
169. Zhang T, Ma Z, Wang R, et al. Thrombin facilitates invasion of ovarian cancer along peritoneum by inducing monocyte differentiation toward tumor-associated macrophage-like cells. Cancer Immunol Immunother. 2010;59:1097–1108.
170. Cho MS, Bottsford-Miller J, Vasquez HG, et al. Platelets increase the proliferation of ovarian cancer cells. Blood. 2012;120:4869–4872.
171. Bottsford-Miller J, Choi HJ, Dalton HJ, et al. Differential platelet levels affect response to taxane-based therapy in ovarian cancer. Clin Cancer Res. 2015;21:602–610.
172. Bunt SK, Mohr AM, Bailey JM, Grandgenett PM, Hollingsworth MA. Rosiglitazone and Gemcitabine in combination reduces immune suppression and modulates T cell populations in pancreatic cancer. Cancer Immunol Immunother. 2012;62:225–236.
173. Vincent J, Mignot G, Chalmin F, et al. 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res. 2010;70:3052–3061.
174. Bruchard M, Mignot G, Derangere V, et al. Chemotherapy-triggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growth. Nat Med. 2013;19:57–64.
175. Ahn GO, Tseng D, Liao CH, Dorie MJ, Czechowicz A, Brown JM. Inhibition of Mac-1 (CD11b/CD18) enhances tumor response to radiation by reducing myeloid cell recruitment. Proc Natl Acad Sci USA. 2010;107:8363–8368.
176. Predina J, Eruslanov E, Judy B, et al. Changes in the local tumor microenvironment in recurrent cancers may explain the failure of vaccines after surgery. Proc Natl Acad Sci USA. 2013;110:E415–E424.
177. Crawford J, Armitage J, Balducci L, et al. Myeloid growth factors. J Natl Compr Canc Netw. 2013;11:1266–1290.
178. Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol. 2006;24:3187–3205.
179. Abrams SI, Waight JD. Identification of a G-CSF-Granulocytic MDSC axis that promotes tumor progression. Oncoimmunology. 2012;1:550–551.
180. Kawano M, Mabuchi S, Matsumoto Y, et al. The significance of G-CSF expression and myeloid-derived suppressor cells in the chemoresistance of uterine cervical cancer. Sci Rep. 2015;5:18217.
181. Takeuchi S, Baghdadi M, Tsuchikawa T, et al. Chemotherapy-derived inflammatory responses accelerate the formation of immunosuppressive myeloid cells in the tissue microenvironment of human pancreatic cancer. Cancer Res. 2015;75:2629–2640.
182. Granot Z, Fridlender ZG. Plasticity beyond cancer cells and the “immunosuppressive switch”. Cancer Res. 2015;75:4441–4445.
183. Andzinski L, Kasnitz N, Stahnke S, et al. Type I IFNs induce anti-tumor polarization of tumor associated neutrophils in mice and human. Int J Cancer. 2016;138:1982–1993.
184. McInturff AM, Cody MJ, Elliott EA, et al. Mammalian target of rapamycin regulates neutrophil extracellular trap formation via induction of hypoxia-inducible factor 1 alpha. Blood. 2012;120:3118–3125.
185. Hakkim A, Fuchs TA, Martinez NE, et al. Activation of the Raf-MEK-ERK pathway is required for neutrophil extracellular trap formation. Nat Chem Biol. 2011;7:75–77.
186. Knight JS, Zhao W, Luo W, et al. Peptidylarginine deiminase inhibition is immunomodulatory and vasculoprotective in murine lupus. J Clin Invest. 2013;123:2981–2993.
187. Knight JS, Luo W, O'Dell AA, et al. Peptidylarginine deiminase inhibition reduces vascular damage and modulates innate immune responses in murine models of atherosclerosis. Circ Res. 2014;114:947–956.
188. Knight JS, Subramanian V, O'Dell AA, et al. Peptidylarginine deiminase inhibition disrupts NET formation and protects against kidney, skin and vascular disease in lupus-prone MRL/lpr mice. Ann Rheum Dis. 2014;74:2199–2206.
189. Shishikura K, Horiuchi T, Sakata N, et al. Prostaglandin E2 inhibits neutrophil extracellular trap formation through production of cyclic AMP. Br J Pharmacol. 2016;173:319–331.
190. Chu D, Zhao Q, Yu J, Zhang F, Zhang H, Wang Z. Nanoparticle targeting of neutrophils for improved cancer immunotherapy. Adv Healthc Mater. 2016;5:1088–1093.
191. Zhang D, Chen G, Manwani D, et al. Neutrophil ageing is regulated by the microbiome. Nature. 2015;525:528–532.
192. Hergott CB, Roche AM, Tamashiro E, et al. Peptidoglycan from the gut microbiota governs the lifespan of circulating phagocytes at homeostasis. Blood. 2016;127:2460–2471.
193. Zitvogel L, Galluzzi L, Viaud S, et al. Cancer and the gut microbiota: an unexpected link. Sci Transl Med. 2015;7:271ps1.
194. Sivan A, Corrales L, Hubert N, et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science. 2015;350:1084–1089.
195. Vetizou M, Pitt JM, Daillere R, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015;350:1079–1084.
196. Netea MG, Latz E, Mills KH, O'Neill LA. Innate immune memory: a paradigm shift in understanding host defense. Nat Immunol. 2015;16:675–679.
197. Cheng SC, Quintin J, Cramer RA, et al. mTOR- and HIF-1alpha-mediated aerobic glycolysis as metabolic basis for trained immunity. Science. 2014;345:1250684.
198. Saeed S, Quintin J, Kerstens HH, et al. Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science. 2014;345:1251086.
199. Chen F, Wu W, Millman A, et al. Neutrophils prime a long-lived effector macrophage phenotype that mediates accelerated helminth expulsion. Nat Immunol. 2014;15:938–946.
200. Netea MG, Joosten LA, Latz E, et al. Trained immunity: a program of innate immune memory in health and disease. Science. 2016;352:aaf1098.