On the origin of myeloid-derived suppressor cells

Oncotarget

Volumn 8, Issue 2, 2017, Pages 3649-3665

  Millrud, Camilla Rydberg ^a   Bergenfelz, Caroline ^a   Leandersson, Karin ^a  

^a LUND UNIVERSITY   (Sweden)

Author keywords

Emergency myelopoiesis; Extramedullary; MDSC origin; Myelopoiesis; Reprogramming

Indexed keywords

CELL ACTIVATION; CELL DIFFERENTIATION; CELL STRUCTURE; GRANULOCYTE; HUMAN; MOLECULAR DYNAMICS; MONOCYTE; MYELOID-DERIVED SUPPRESSOR CELL; MYELOPOIESIS; NEUTROPHIL; NONHUMAN; PHENOTYPE; REVIEW; SIGNAL TRANSDUCTION; WOUND HEALING; ANIMAL; BONE MARROW CELL; CYTOLOGY; EXTRAMEDULLARY HEMATOPOIESIS; GENE EXPRESSION REGULATION; GENETICS; IMMUNOLOGY; IMMUNOMODULATION; LEUKOCYTE ACTIVATION; METABOLISM; NUCLEAR REPROGRAMMING; PHYSIOLOGY;

COLONY STIMULATING FACTOR;

ANIMALS; CELL DIFFERENTIATION; CELLULAR REPROGRAMMING; COLONY-STIMULATING FACTORS; GENE EXPRESSION REGULATION; GRANULOCYTES; HEMATOPOIESIS, EXTRAMEDULLARY; HUMANS; IMMUNOMODULATION; MONOCYTES; MYELOID CELLS; MYELOID-DERIVED SUPPRESSOR CELLS; MYELOPOIESIS; NEUTROPHIL ACTIVATION; NEUTROPHILS; PHENOTYPE; SIGNAL TRANSDUCTION;

EID: 85009822955     PISSN: None     EISSN: 19492553     Source Type: Journal    
DOI: 10.18632/oncotarget.12278     Document Type: Review

References (143)

1. Gabrilovich DI, Bronte V, Chen SH, Colombo MP, Ochoa A, Ostrand-Rosenberg S, Schreiber H. The terminology issue for myeloid-derived suppressor cells. Cancer Res. 2007; 67: 425; author reply 6. doi: 10.1158/0008-5472. CAN-06-3037
2. Ostrand-Rosenberg S, Sinha P. Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol. 2009; 182: 4499-506. doi: 10.4049/jimmunol.0802740
3. Cuenca AG, Delano MJ, Kelly-Scumpia KM, Moreno C, Scumpia PO, Laface DM, Heyworth PG, Efron PA, Moldawer LL. A paradoxical role for myeloid-derived suppressor cells in sepsis and trauma. Mol Med. 2011; 17: 281-92. doi: 10.2119/molmed.2010.00178
4. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009; 9: 162-74. doi: 10.1038/nri2506
5. Poschke I, Kiessling R. On the armament and appearances of human myeloid-derived suppressor cells. Clin Immunol. 2012; 144: 250-68. doi: 10.1016/j.clim.2012.06.003
6. Talmadge JE. Pathways mediating the expansion and immunosuppressive activity of myeloid-derived suppressor cells and their relevance to cancer therapy. Clin Cancer Res. 2007; 13: 5243-8. doi: 10.1158/1078-0432.CCR-07-0182
7. Ko JS, Bukowski RM, Fincke JH. Myeloid-derived suppressor cells: a novel therapeutic target. Curr Oncol Rep. 2009; 11: 87-93
8. Sinha P, Clements VK, Bunt SK, Albelda SM, Ostrand-Rosenberg S. Cross-talk between myeloid-derived suppressor cells and macrophages subverts tumor immunity toward a type 2 response. J Immunol. 2007; 179: 977-83
9. Yang L, Huang J, Ren X, Gorska AE, Chytil A, Aakre M, Carbone DP, Matrisian LM, Richmond A, Lin PC, Moses HL. Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. Cancer Cell. 2008; 13: 23-35. doi: 10.1016/j.ccr.2007.12.004
10. Murdoch C, Muthana M, Coffelt SB, Lewis CE. The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer. 2008; 8: 618-31. doi: 10.1038/nrc2444
11. Mandruzzato S, Solito S, Falisi E, Francescato S, Chiarion-Sileni V, Mocellin S, Zanon A, Rossi CR, Nitti D, Bronte V, Zanovello P. IL4Ralpha+ myeloid-derived suppressor cell expansion in cancer patients. J Immunol. 2009; 182: 6562-8. doi: 10.4049/jimmunol.0803831
12. Khaled YS, Ammori BJ, Elkord E. Increased levels of granulocytic myeloid-derived suppressor cells in peripheral blood and tumour tissue of pancreatic cancer patients. J Immunol Res. 2014; 2014: 879897. doi: 10.1155/2014/879897
13. Bergenfelz C, Larsson AM, von Stedingk K, Gruvberger-Saal S, Aaltonen K, Jansson S, Jernstrom H, Janols H, Wullt M, Bredberg A, Ryden L, Leandersson K. Systemic Monocytic-MDSCs Are Generated from Monocytes and Correlate with Disease Progression in Breast Cancer Patients. PLoS One. 2015; 10: e0127028. doi: 10.1371/journal.pone.0127028
14. Diaz-Montero CM, Salem ML, Nishimura MI, Garrett-Mayer E, Cole DJ, Montero AJ. Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicincyclophosphamide chemotherapy. Cancer Immunol Immunother. 2009; 58: 49-59. doi: 10.1007/s00262-008-0523-4
15. Wang L, Chang EW, Wong SC, Ong SM, Chong DQ, Ling KL. Increased myeloid-derived suppressor cells in gastric cancer correlate with cancer stage and plasma S100A8/A9 proinflammatory proteins. J Immunol. 2013; 190: 794-804. doi: 10.4049/jimmunol.1202088
16. Sun HL, Zhou X, Xue YF, Wang K, Shen YF, Mao JJ, Guo HF, Miao ZN. Increased frequency and clinical significance of myeloid-derived suppressor cells in human colorectal carcinoma. World J Gastroenterol. 2012; 18: 3303-9. doi: 10.3748/wjg.v18.i25.3303
17. Zhang B, Wang Z, Wu L, Zhang M, Li W, Ding J, Zhu J, Wei H, Zhao K. Circulating and tumor-infiltrating myeloid-derived suppressor cells in patients with colorectal carcinoma. PLoS One. 2013; 8: e57114. doi: 10.1371/journal.pone.0057114
18. Huang A, Zhang B, Wang B, Zhang F, Fan KX, Guo YJ. Increased CD14(+)HLA-DR (-/low) myeloid-derived suppressor cells correlate with extrathoracic metastasis and poor response to chemotherapy in non-small cell lung cancer patients. Cancer Immunol Immunother. 2013; 62: 1439-51. doi: 10.1007/s00262-013-1450-6
19. Shen P, Wang A, He M, Wang Q, Zheng S. Increased circulating Lin(-/low) CD33(+) HLA-DR(-) myeloidderived suppressor cells in hepatocellular carcinoma patients. Hepatol Res. 2014; 44: 639-50. doi: 10.1111/hepr.12167
20. Antonia SJ, Mirza N, Fricke I, Chiappori A, Thompson P, Williams N, Bepler G, Simon G, Janssen W, Lee JH, Menander K, Chada S, Gabrilovich DI. Combination of p53 cancer vaccine with chemotherapy in patients with extensive stage small cell lung cancer. Clin Cancer Res. 2006; 12: 878-87. doi: 10.1158/1078-0432.CCR-05-2013
21. Walter S, Weinschenk T, Stenzl A, Zdrojowy R, Pluzanska A, Szczylik C, Staehler M, Brugger W, Dietrich PY, Mendrzyk R, Hilf N, Schoor O, Fritsche J, et al. Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival. Nat Med. 2012; 18: 1254-61. doi: 10.1038/nm.2883
22. Kusmartsev S, Gabrilovich DI. Immature myeloid cells and cancer-associated immune suppression. Cancer Immunol Immunother. 2002; 51: 293-8. doi: 10.1007/s00262-002-0280-8
23. Meirow Y, Kanterman J, Baniyash M. Paving the Road to Tumor Development and Spreading: Myeloid-Derived Suppressor Cells are Ruling the Fate. Front Immunol. 2015; 6: 523. doi: 10.3389/fimmu.2015.00523
24. Sander LE, Sackett SD, Dierssen U, Beraza N, Linke RP, Muller M, Blander JM, Tacke F, Trautwein C. Hepatic acute-phase proteins control innate immune responses during infection by promoting myeloid-derived suppressor cell function. J Exp Med. 2010; 207: 1453-64. doi: 10.1084/jem.20091474
25. Derive M, Bouazza Y, Alauzet C, Gibot S. Myeloid-derived suppressor cells control microbial sepsis. Intensive Care Med. 2012; 38: 1040-9. doi: 10.1007/s00134-012-2574-4
26. Biswas SK, Lopez-Collazo E. Endotoxin tolerance: new mechanisms, molecules and clinical significance. Trends Immunol. 2009; 30: 475-87. doi: 10.1016/j.it.2009.07.009
27. Peranzoni E, Zilio S, Marigo I, Dolcetti L, Zanovello P, Mandruzzato S, Bronte V. Myeloid-derived suppressor cell heterogeneity and subset definition. Curr Opin Immunol. 2010; 22: 238-44. doi: 10.1016/j.coi.2010.01.021
28. Youn JI, Gabrilovich DI. The biology of myeloid-derived suppressor cells: the blessing and the curse of morphological and functional heterogeneity. Eur J Immunol. 2010; 40: 2969-75. doi: 10.1002/eji.201040895
29. Pillay J, Tak T, Kamp VM, Koenderman L. Immune suppression by neutrophils and granulocytic myeloidderived suppressor cells: similarities and differences. Cell Mol Life Sci. 2013; 70: 3813-27. doi: 10.1007/s00018-013-1286-4
30. Fan HK, Cook JA. Molecular mechanisms of endotoxin tolerance. Journal of Endotoxin Research. 2004; 10: 71-84. doi: 10.1179/096805104225003997
31. Ruppert J, Schutt C, Ostermeier D, Peters JH. Down-Regulation and Release of Cd14 on Human Monocytes by Il-4 Depends on the Presence of Serum or Gm-Csf. Dendritic Cells in Fundamental and Clinical Immunology. 1993; 329: 281-6
32. Sinistro A, Ciaprini C, Natoli S, Sussarello E, Carducci FC, Almerighi C, Capozzi M, Bolacchi F, Rocchi G, Bergamini A. Lipopolysaccharide desensitizes monocytesmacrophages to CD40 ligand stimulation. Immunology. 2007; 122: 362-70. doi: 10.1111/j.1365-2567.2007.02648.x
33. Xiu B, Lin Y, Grote DM, Ziesmer SC, Gustafson MP, Maas ML, Zhang Z, Dietz AB, Porrata LF, Novak AJ, Liang AB, Yang ZZ, Ansell SM. IL-10 induces the development of immunosuppressive CD14(+) HLA-DRlow/-monocytes in B-cell non-Hodgkin lymphoma. Blood Cancer Journal. 2015; 5. doi: ARTN e328 10.1038/bcj.2015.56
34. Landmann R, Ludwig C, Obrist R, Obrecht JP. Effect of cytokines and lipopolysaccharide on CD14 antigen expression in human monocytes and macrophages. J Cell Biochem. 1991; 47: 317-29. doi: 10.1002/jcb.240470406
35. Lahat N, Rahat MA, Ballan M, Weiss-Cerem L, Engelmayer M, Bitterman H. Hypoxia reduces CD80 expression on monocytes but enhances their LPS-stimulated TNF-alpha secretion. Journal of Leukocyte Biology. 2003; 74: 197-205. doi: 10.1189/jlb.0303105
36. Mancino A, Schioppa T, Larghi P, Pasqualini F, Nebuloni M, Chen IH, Sozzani S, Austyn JM, Mantovani A, Sica A. Divergent effects of hypoxia on dendritic cell functions. Blood. 2008; 112: 3723-34. doi: 10.1182/blood-2008-02-142091
37. Filipazzi P, Huber V, Rivoltini L. Phenotype, function and clinical implications of myeloid-derived suppressor cells in cancer patients. Cancer Immunol Immunother. 2012; 61: 255-63. doi: 10.1007/s00262-011-1161-9
38. Feng PH, Lee KY, Chang YL, Chan YF, Kuo LW, Lin TY, Chung FT, Kuo CS, Yu CT, Lin SM, Wang CH, Chou CL, Huang CD, et al. CD14(+)S100A9(+) monocytic myeloidderived suppressor cells and their clinical relevance in nonsmall cell lung cancer. Am J Respir Crit Care Med. 2012; 186: 1025-36. doi: 10.1164/rccm.201204-0636OC
39. Zhao F, Hoechst B, Duffy A, Gamrekelashvili J, Fioravanti S, Manns MP, Greten TF, Korangy F. S100A9 a new marker for monocytic human myeloid-derived suppressor cells. Immunology. 2012; 136: 176-83. doi: 10.1111/j.1365-2567.2012.03566.x
40. Mundy-Bosse BL, Young GS, Bauer T, Binkley E, Bloomston M, Bill MA, Bekaii-Saab T, Carson WE, 3rd, Lesinski GB. Distinct myeloid suppressor cell subsets correlate with plasma IL-6 and IL-10 and reduced interferon-alpha signaling in CD4(+) T cells from patients with GI malignancy. Cancer Immunol Immunother. 2011; 60: 1269-79. doi: 10.1007/s00262-011-1029-z
41. Mirza N, Fishman M, Fricke I, Dunn M, Neuger AM, Frost TJ, Lush RM, Antonia S, Gabrilovich DI. All-trans-retinoic acid improves differentiation of myeloid cells and immune response in cancer patients. Cancer Res. 2006; 66: 9299-307. doi: 10.1158/0008-5472.CAN-06-1690
42. Finke J, Ko J, Rini B, Rayman P, Ireland J, Cohen P. MDSC as a mechanism of tumor escape from sunitinib mediated anti-angiogenic therapy. Int Immunopharmacol. 2011; 11: 856-61. doi: 10.1016/j.intimp.2011.01.030
43. Gabitass RF, Annels NE, Stocken DD, Pandha HA, Middleton GW. Elevated myeloid-derived suppressor cells in pancreatic, esophageal and gastric cancer are an independent prognostic factor and are associated with significant elevation of the Th2 cytokine interleukin-13. Cancer Immunol Immunother. 2011; 60: 1419-30. doi: 10.1007/s00262-011-1028-0
44. van Cruijsen H, Hoekman K, Stam AG, van den Eertwegh AJ, Kuenen BC, Scheper RJ, Giaccone G, de Gruijl TD. Defective differentiation of myeloid and plasmacytoid dendritic cells in advanced cancer patients is not normalized by tyrosine kinase inhibition of the vascular endothelial growth factor receptor. Clin Dev Immunol. 2007; 2007:17315 doi: 10.1155/2007/17315
45. Zea AH, Rodriguez PC, Atkins MB, Hernandez C, Signoretti S, Zabaleta J, McDermott D, Quiceno D, Youmans A, O'Neill A, Mier J, Ochoa AC. Arginaseproducing myeloid suppressor cells in renal cell carcinoma patients: a mechanism of tumor evasion. Cancer Res. 2005; 65: 3044-8. doi: 10.1158/0008-5472.CAN-04-4505
46. Nagaraj S, Gupta K, Pisarev V, Kinarsky L, Sherman S, Kang L, Herber DL, Schneck J, Gabrilovich DI. Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer. Nat Med. 2007; 13: 828-35. doi: 10.1038/nm1609
47. Dietlin TA, Hofman FM, Lund BT, Gilmore W, Stohlman SA, van der Veen RC. Mycobacteria-induced Gr-1+ subsets from distinct myeloid lineages have opposite effects on T cell expansion. J Leukoc Biol. 2007; 81: 1205-12. doi: 10.1189/jlb.1006640
48. Condamine T, Mastio J, Gabrilovich DI. Transcriptional regulation of myeloid-derived suppressor cells. J Leukoc Biol. 2015; 98: 913-22. doi: 10.1189/jlb.4RI0515-204R
49. Talmadge JE, Gabrilovich DI. History of myeloid-derived suppressor cells. Nat Rev Cancer. 2013; 13: 739-52. doi: 10.1038/nrc3581
50. Rashid OM, Nagahashi M, Ramachandran S, Graham L, Yamada A, Spiegel S, Bear HD, Takabe K. Resection of the primary tumor improves survival in metastatic breast cancer by reducing overall tumor burden. Surgery. 2013; 153: 771-8. doi: 10.1016/j.surg.2013.02.002
51. Salvadori S, Martinelli G, Zier K. Resection of solid tumors reverses T cell defects and restores protective immunity. J Immunol. 2000; 164: 2214-20
52. Bayne LJ, Beatty GL, Jhala N, Clark CE, Rhim AD, Stanger BZ, Vonderheide RH. Tumor-Derived Granulocyte-Macrophage Colony-Stimulating Factor Regulates Myeloid Inflammation and T Cell Immunity in Pancreatic Cancer. Cancer Cell. 2012; 21: 822-35. doi: 10.1016/j. ccr.2012.04.025
53. Bronte V, Chappell DB, Apolloni E, Cabrelle A, Wang M, Hwu P, Restifo NP. Unopposed production of granulocytemacrophage colony-stimulating factor by tumors inhibits CD8+ T cell responses by dysregulating antigen-presenting cell maturation. J Immunol. 1999; 162: 5728-37
54. Dolcetti L, Peranzoni E, Ugel S, Marigo I, Fernandez Gomez A, Mesa C, Geilich M, Winkels G, Traggiai E, Casati A, Grassi F, Bronte V. Hierarchy of immunosuppressive strength among myeloid-derived suppressor cell subsets is determined by GM-CSF. Eur J Immunol. 2010; 40: 22-35. doi: 10.1002/eji.200939903
55. Morales JK, Kmieciak M, Knutson KL, Bear HD, Manjili MH. GM-CSF is one of the main breast tumor-derived soluble factors involved in the differentiation of CD11b-Gr1-bone marrow progenitor cells into myeloid-derived suppressor cells. Breast Cancer Res Treat. 2010; 123: 39-49. doi: 10.1007/s10549-009-0622-8
56. 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, et al. Granulocyte-colony stimulating factor promotes lung metastasis through mobilization of Ly6G+Ly6C+ granulocytes. Proc Natl Acad Sci U S A. 2010; 107: 21248-55. doi: 10.1073/pnas.1015855107
57. Waight JD, Hu Q, Miller A, Liu S, Abrams SI. Tumorderived G-CSF facilitates neoplastic growth through a granulocytic myeloid-derived suppressor cell-dependent mechanism. PLoS One. 2011; 6: e27690. doi: 10.1371/journal.pone.0027690
58. Menetrier-Caux C, Montmain G, Dieu MC, Bain C, Favrot MC, Caux C, Blay JY. Inhibition of the differentiation of dendritic cells from CD34(+) progenitors by tumor cells: role of interleukin-6 and macrophage colony-stimulating factor. Blood. 1998; 92: 4778-91
59. Kumar V, Patel S, Tcyganov E, Gabrilovich DI. The Nature of Myeloid-Derived Suppressor Cells in the Tumor Microenvironment. Trends Immunol. 2016; 37: 208-20. doi: 10.1016/j.it.2016.01.004
60. Delano MJ, Scumpia PO, Weinstein JS, Coco D, Nagaraj S, Kelly-Scumpia KM, O'Malley KA, Wynn JL, Antonenko S, Al-Quran SZ, Swan R, Chung CS, Atkinson MA, et al. MyD88-dependent expansion of an immature GR-1(+) CD11b(+) population induces T cell suppression and Th2 polarization in sepsis. J Exp Med. 2007; 204: 1463-74. doi: 10.1084/jem.20062602
61. Makarenkova VP, Bansal V, Matta BM, Perez LA, Ochoa JB. CD11b+/Gr-1+ myeloid suppressor cells cause T cell dysfunction after traumatic stress. J Immunol. 2006; 176: 2085-94
62. Kusmartsev SA, Li Y, Chen SH. Gr-1+ myeloid cells derived from tumor-bearing mice inhibit primary T cell activation induced through CD3/CD28 costimulation. J Immunol. 2000; 165: 779-85
63. Schmidt-Wolf IG, Dejbakhsh-Jones S, Ginzton N, Greenberg P, Strober S. T-cell subsets and suppressor cells in human bone marrow. Blood. 1992; 80: 3242-50
64. Song X, Krelin Y, Dvorkin T, Bjorkdahl O, Segal S, Dinarello CA, Voronov E, Apte RN. CD11b+/Gr-1+ immature myeloid cells mediate suppression of T cells in mice bearing tumors of IL-1beta-secreting cells. J Immunol. 2005; 175: 8200-8
65. Sinha P, Okoro C, Foell D, Freeze HH, Ostrand-Rosenberg S, Srikrishna G. Proinflammatory S100 proteins regulate the accumulation of myeloid-derived suppressor cells. J Immunol. 2008; 181: 4666-75
66. Gabrilovich DI, Ostrand-Rosenberg S, Bronte V. Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol. 2012; 12: 253-68. doi: 10.1038/nri3175
67. Panopoulos AD, Watowich SS. Granulocyte colonystimulating factor: molecular mechanisms of action during steady state and 'emergency' hematopoiesis. Cytokine. 2008; 42: 277-88. doi: 10.1016/j.cyto.2008.03.002
68. Wicks IP, Roberts AW. Targeting GM-CSF in inflammatory diseases. Nat Rev Rheumatol. 2016; 12: 37-48. doi: 10.1038/nrrheum.2015.161
69. Hamilton JA. Colony-stimulating factors in inflammation and autoimmunity. Nat Rev Immunol. 2008; 8: 533-44. doi: 10.1038/nri2356
70. Marigo I, Bosio E, Solito S, Mesa C, Fernandez A, Dolcetti L, Ugel S, Sonda N, Bicciato S, Falisi E, Calabrese F, Basso G, Zanovello P, et al. Tumor-induced tolerance and immune suppression depend on the C/EBPbeta transcription factor. Immunity. 2010; 32: 790-802. doi: 10.1016/j. immuni.2010.05.010
71. 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, et al. A human promyelocytic-like population is responsible for the immune suppression mediated by myeloid-derived suppressor cells. Blood. 2011; 118: 2254-65. doi: 10.1182/blood-2010-12-325753
72. Highfill SL, Rodriguez PC, Zhou Q, Goetz CA, Koehn BH, Veenstra R, Taylor PA, Panoskaltsis-Mortari A, Serody JS, Munn DH, Tolar J, Ochoa AC, Blazar BR. Bone marrow myeloid-derived suppressor cells (MDSCs) inhibit graftversus-host disease (GVHD) via an arginase-1-dependent mechanism that is up-regulated by interleukin-13. Blood. 2010; 116: 5738-47. doi: 10.1182/blood-2010-06-287839
73. Sinha P, Clements VK, Fulton AM, Ostrand-Rosenberg S. Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells. Cancer Res. 2007; 67: 4507-13. doi: 10.1158/0008-5472.CAN-06-4174
74. American Society of Clinical Oncology. Recommendations for the use of hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines. J Clin Oncol. 1994; 12: 2471-508
75. Ozer H, Armitage JO, Bennett CL, Crawford J, Demetri GD, Pizzo PA, Schiffer CA, Smith TJ, Somlo G, Wade JC, Wade JL, 3rd, Winn RJ, Wozniak AJ, et al. 2000 update of recommendations for the use of hematopoietic colonystimulating factors: evidence-based, clinical practice guidelines. American Society of Clinical Oncology Growth Factors Expert Panel. J Clin Oncol. 2000; 18: 3558-85. doi:
76. Wu FP, Westphal JR, Hoekman K, Mels AK, Statius Muller MG, de Waal RW, Beelen RH, van Leeuwen PA, Meijer S, Cuesta MA. The effects of surgery, with or without rhGM-CSF, on the angiogenic profile of patients treated for colorectal carcinoma. Cytokine. 2004; 25: 68-72
77. Filipazzi P, Valenti R, Huber V, Pilla L, Canese P, Iero M, Castelli C, Mariani L, Parmiani G, Rivoltini L. Identification of a new subset of myeloid suppressor cells in peripheral blood of melanoma patients with modulation by a granulocyte-macrophage colony-stimulation factor-based antitumor vaccine. J Clin Oncol. 2007; 25: 2546-53. doi: 10.1200/JCO.2006.08.5829
78. Annels NE, Shaw VE, Gabitass RF, Billingham L, Corrie P, Eatock M, Valle J, Smith D, Wadsley J, Cunningham D, Pandha H, Neoptolemos JP, Middleton G. The effects of gemcitabine and capecitabine combination chemotherapy and of low-dose adjuvant GM-CSF on the levels of myeloid-derived suppressor cells in patients with advanced pancreatic cancer. Cancer Immunol Immunother. 2014; 63: 175-83. doi: 10.1007/s00262-013-1502-y
79. Tsuchiya Y, Igarashi M, Suzuki R, Kumagai K. Production of colony-stimulating factor by tumor cells and the factormediated induction of suppressor cells. J Immunol. 1988; 141: 699-708
80. Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motifcarrying immunoreceptor. Immunity. 1999; 11: 141-51
81. Oghiso Y, Yamada Y, Ando K, Ishihara H, Shibata Y. Differential induction of prostaglandin E2-dependent and-independent immune suppressor cells by tumor-derived GM-CSF and M-CSF. J Leukoc Biol. 1993; 53: 86-92
82. Abrams SI, Waight JD. Identification of a G-CSFGranulocytic MDSC axis that promotes tumor progression. Oncoimmunology. 2012; 1: 550-1
83. Stromnes IM, Greenberg PD, Hingorani SR. Molecular pathways: myeloid complicity in cancer. Clin Cancer Res. 2014; 20: 5157-70. doi: 10.1158/1078-0432.CCR-13-0866
84. Pak AS, Wright MA, Matthews JP, Collins SL, Petruzzelli GJ, Young MR. Mechanisms of immune suppression in patients with head and neck cancer: presence of CD34(+) cells which suppress immune functions within cancers that secrete granulocyte-macrophage colony-stimulating factor. Clin Cancer Res. 1995; 1: 95-103
85. Cheers C, Haigh AM, Kelso A, Metcalf D, Stanley ER, Young AM. Production of Colony-Stimulating Factors (Csfs) during Infection-Separate Determinations of Macrophage-Csf, Granulocyte-Csf, Granulocyte-Macrophage-Csf, and Multi-Csf. Infection and Immunity. 1988; 56: 247-51
86. Kawakami M, Tsutsumi H, Kumakawa T, Abe H, Hirai M, Kurosawa S, Mori M, Fukushima M. Levels of Serum Granulocyte Colony-Stimulating Factor in Patients with Infections. Blood. 1990; 76: 1962-4
87. Ueha S, Shand FH, Matsushima K. Myeloid cell population dynamics in healthy and tumor-bearing mice. Int Immunopharmacol. 2011; 11: 783-8. doi: 10.1016/j. intimp.2011.03.003
88. Almand B, Clark JI, Nikitina E, van Beynen J, English NR, Knight SC, Carbone DP, Gabrilovich DI. Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J Immunol. 2001; 166: 678-89
89. Allavena P, Piemonti L, Longoni D, Bernasconi S, Stoppacciaro A, Ruco L, Mantovani A. IL-10 prevents the differentiation of monocytes to dendritic cells but promotes their maturation to macrophages. Eur J Immunol. 1998; 28: 359-69. doi: 10.1002/(SICI)1521-4141(199801)28:01<359::AIDIMMU359>3.0.CO;2-4
90. Cheng P, Corzo CA, Luetteke N, Yu B, Nagaraj S, Bui MM, Ortiz M, Nacken W, Sorg C, Vogl T, Roth J, Gabrilovich DI. Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein. J Exp Med. 2008; 205: 2235-49. doi: 10.1084/jem.20080132
91. Gabrilovich D, Ishida T, Oyama T, Ran S, Kravtsov V, Nadaf S, Carbone DP. Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood. 1998; 92: 4150-66
92. Chalmin F, Ladoire S, Mignot G, Vincent J, Bruchard M, Remy-Martin JP, Boireau W, Rouleau A, Simon B, Lanneau D, De Thonel A, Multhoff G, Hamman A, et al. Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells. J Clin Invest. 2010; 120: 457-71. doi: 10.1172/JCI40483
93. Strauss L, Sangaletti S, Consonni FM, Szebeni G, Morlacchi S, Totaro MG, Porta C, Anselmo A, Tartari S, Doni A, Zitelli F, Tripodo C, Colombo MP, et al. RORC1 Regulates Tumor-Promoting "Emergency" Granulo-Monocytopoiesis. Cancer Cell. 2015; 28: 253-69. doi: 10.1016/j.ccell.2015.07.006
94. Young MR, Newby M, Wepsic HT. Hematopoiesis and suppressor bone marrow cells in mice bearing large metastatic Lewis lung carcinoma tumors. Cancer Res. 1987; 47: 100-5
95. Kim CH. Homeostatic and pathogenic extramedullary hematopoiesis. J Blood Med. 2010; 1: 13-9. doi: 10.2147/JBM.S7224
96. Massberg S, Schaerli P, Knezevic-Maramica I, Kollnberger M, Tubo N, Moseman EA, Huff IV, Junt T, Wagers AJ, Mazo IB, von Andrian UH. Immunosurveillance by hematopoietic progenitor cells trafficking through blood, lymph, and peripheral tissues. Cell. 2007; 131: 994-1008. doi: 10.1016/j.cell.2007.09.047
97. Skabytska Y, Wolbing F, Gunther C, Koberle M, Kaesler S, Chen KM, Guenova E, Demircioglu D, Kempf WE, Volz T, Rammensee HG, Schaller M, Rocken M, et al. Cutaneous innate immune sensing of Toll-like receptor 2-6 ligands suppresses T cell immunity by inducing myeloidderived suppressor cells. Immunity. 2014; 41: 762-75. doi: 10.1016/j.immuni.2014.10.009
98. Greifenberg V, Ribechini E, Rossner S, Lutz MB. Myeloidderived suppressor cell activation by combined LPS and IFN-gamma treatment impairs DC development. Eur J Immunol. 2009; 39: 2865-76. doi: 10.1002/eji.200939486
99. O'Malley DP. Benign extramedullary myeloid proliferations. Mod Pathol. 2007; 20: 405-15. doi: 10.1038/modpathol.3800768
100. Platzbecker U, Prange-Krex G, Bornhauser M, Koch R, Soucek S, Aikele P, Haack A, Haag C, Schuler U, Berndt A, Rutt C, Ehninger G, Holig K. Spleen enlargement in healthy donors during G-CSF mobilization of PBPCs. Transfusion. 2001; 41: 184-9
101. Stroncek D, Shawker T, Follmann D, Leitman SF. G-CSFinduced spleen size changes in peripheral blood progenitor cell donors. Transfusion. 2003; 43: 609-13
102. Picardi M, De Rosa G, Selleri C, Scarpato N, Soscia E, Martinelli V, Ciancia R, Rotoli B. Spleen enlargement following recombinant human granulocyte colonystimulating factor administration for peripheral blood stem cell mobilization. Haematologica. 2003; 88: 794-800. doi:
103. Molineux G, Pojda Z, Dexter TM. A comparison of hematopoiesis in normal and splenectomized mice treated with granulocyte colony-stimulating factor. Blood. 1990; 75: 563-9
104. Falzetti F, Aversa F, Minelli O, Tabilio A. Spontaneous rupture of spleen during peripheral blood stem-cell mobilisation in a healthy donor. Lancet. 1999; 353: 555. doi: 10.1016/S0140-6736(99)00268-8
105. Kalinski P, Hilkens CM, Snijders A, Snijdewint FG, Kapsenberg ML. IL-12-deficient dendritic cells, generated in the presence of prostaglandin E2, promote type 2 cytokine production in maturing human naive T helper cells. J Immunol. 1997; 159: 28-35
106. Obermajer N, Muthuswamy R, Lesnock J, Edwards RP, Kalinski P. Positive feedback between PGE2 and COX2 redirects the differentiation of human dendritic cells toward stable myeloid-derived suppressor cells. Blood. 2011; 118: 5498-505. doi: 10.1182/blood-2011-07-365825
107. Mao Y, Poschke I, Wennerberg E, Pico de Coana Y, Egyhazi Brage S, Schultz I, Hansson J, Masucci G, Lundqvist A, Kiessling R. Melanoma-educated CD14+ cells acquire a myeloid-derived suppressor cell phenotype through COX-2-dependent mechanisms. Cancer Res. 2013; 73: 3877-87. doi: 10.1158/0008-5472.CAN-12-4115
108. Gabrilovich DI, Corak J, Ciernik IF, Kavanaugh D, Carbone DP. Decreased antigen presentation by dendritic cells in patients with breast cancer. Clin Cancer Res. 1997; 3: 483-90
109. Kusmartsev S, Cheng F, Yu B, Nefedova Y, Sotomayor E, Lush R, Gabrilovich D. All-trans-retinoic acid eliminates immature myeloid cells from tumor-bearing mice and improves the effect of vaccination. Cancer Res. 2003; 63: 4441-9
110. Kusmartsev S, Su Z, Heiser A, Dannull J, Eruslanov E, Kubler H, Yancey D, Dahm P, Vieweg J. Reversal of myeloid cell-mediated immunosuppression in patients with metastatic renal cell carcinoma. Clin Cancer Res. 2008; 14: 8270-8. doi: 10.1158/1078-0432.CCR-08-0165
111. Garrity T, Pandit R, Wright MA, Benefield J, Keni S, Young MRI. Increased presence of CD34(+) cells in the peripheral blood of head and neck cancer patients and their differentiation into dendritic cells. International Journal of Cancer. 1997; 73: 663-9. doi: Doi 10.1002/(Sici)1097-0215(19971127)73:5<663::Aid-Ijc9>3.0.Co;2-V
112. Lathers DMR, Clark JI, Achille NJ, Young MRI. Phase 1B study to improve immune responses in head and neck cancer patients using escalating doses of 25-hydroxyvitamin D-3. Cancer Immunology Immunotherapy. 2004; 53: 422-30. doi: 10.1007/s00262-003-0459-7
113. Sade-Feldman M, Kanterman J, Ish-Shalom E, Elnekave M, Horwitz E, Baniyash M. Tumor Necrosis Factoralpha Blocks Differentiation and Enhances Suppressive Activity of Immature Myeloid Cells during Chronic Inflammation. Immunity. 2013; 38: 541-54. doi: 10.1016/j. immuni.2013.02.007
114. Movahedi K, Guilliams M, Van den Bossche J, Van den Bergh R, Gysemans C, Beschin A, De Baetselier P, Van Ginderachter JA. Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity. Blood. 2008; 111: 4233-44. doi: 10.1182/blood-2007-07-099226
115. Umemura N, Saio M, Suwa T, Kitoh Y, Bai J, Nonaka K, Ouyang GF, Okada M, Balazs M, Adany R, Shibata T, Takami T. Tumor-infiltrating myeloid-derived suppressor cells are pleiotropic-inflamed monocytes/macrophages that bear M1-and M2-type characteristics. J Leukoc Biol. 2008; 83: 1136-44. doi: 10.1189/jlb.0907611
116. Poschke I, Mougiakakos D, Hansson J, Masucci GV, Kiessling R. Immature immunosuppressive CD14+HLADR-/low cells in melanoma patients are Stat3hi and overexpress CD80, CD83, and DC-sign. Cancer Res. 2010; 70: 4335-45. doi: 10.1158/0008-5472.CAN-09-3767
117. 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. HIF-1alpha regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J Exp Med. 2010; 207: 2439-53. doi: 10.1084/jem.20100587
118. Pena OM, Pistolic J, Raj D, Fjell CD, Hancock RE. Endotoxin tolerance represents a distinctive state of alternative polarization (M2) in human mononuclear cells. J Immunol. 2011; 186: 7243-54. doi: 10.4049/jimmunol.1001952
119. Porta C, Rimoldi M, Raes G, Brys L, Ghezzi P, Di Liberto D, Dieli F, Ghisletti S, Natoli G, De Baetselier P, Mantovani A, Sica A. Tolerance and M2 (alternative) macrophage polarization are related processes orchestrated by p50 nuclear factor kappaB. Proc Natl Acad Sci U S A. 2009; 106: 14978-83. doi: 10.1073/pnas.0809784106
120. Bergenfelz C, Medrek C, Ekstrom E, Jirstrom K, Janols H, Wullt M, Bredberg A, Leandersson K. Wnt5a induces a tolerogenic phenotype of macrophages in sepsis and breast cancer patients. J Immunol. 2012; 188: 5448-58. doi: 10.4049/jimmunol.1103378
121. Goldsmith M, Avni D, Ernst O, Glucksam Y, Levy-Rimler G, Meijler MM, Zor T. Synergistic IL-10 induction by LPS and the ceramide-1-phosphate analog PCERA-1 is mediated by the cAMP and p38 MAP kinase pathways. Mol Immunol. 2009; 46: 1979-87. doi: 10.1016/j.molimm.2009.03.009
122. Nemeth K, Leelahavanichkul A, Yuen PS, Mayer B, Parmelee A, Doi K, Robey PG, Leelahavanichkul K, Koller BH, Brown JM, Hu X, Jelinek I, Star RA, et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med. 2009; 15: 42-9. doi: 10.1038/nm.1905
123. Ray A, Chakraborty K, Ray P. Immunosuppressive MDSCs induced by TLR signaling during infection and role in resolution of inflammation. Front Cell Infect Microbiol. 2013; 3: 52. doi: 10.3389/fcimb.2013.00052
124. Bianchi ME. DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol. 2007; 81: 1-5. doi: 10.1189/jlb.0306164
125. Rodrigues JC, Gonzalez GC, Zhang L, Ibrahim G, Kelly JJ, Gustafson MP, Lin Y, Dietz AB, Forsyth PA, Yong VW, Parney IF. Normal human monocytes exposed to glioma cells acquire myeloid-derived suppressor cell-like properties. Neuro Oncol. 2010; 12: 351-65. doi: 10.1093/neuonc/nop023
126. Fang Z, Li J, Yu X, Zhang D, Ren G, Shi B, Wang C, Kosinska AD, Wang S, Zhou X, Kozlowski M, Hu Y, Yuan Z. Polarization of Monocytic Myeloid-Derived Suppressor Cells by Hepatitis B Surface Antigen Is Mediated via ERK/IL-6/STAT3 Signaling Feedback and Restrains the Activation of T Cells in Chronic Hepatitis B Virus Infection. J Immunol. 2015; 195: 4873-83. doi: 10.4049/jimmunol.1501362
127. Mao Y, Sarhan D, Steven A, Seliger B, Kiessling R, Lundqvist A. Inhibition of tumor-derived prostaglandin-e2 blocks the induction of myeloid-derived suppressor cells and recovers natural killer cell activity. Clin Cancer Res. 2014; 20: 4096-106. doi: 10.1158/1078-0432.CCR-14-0635
128. Janols H, Bergenfelz C, Allaoui R, Larsson AM, Ryden L, Bjornsson S, Janciauskiene S, Wullt M, Bredberg A, Leandersson K. A high frequency of MDSCs in sepsis patients, with the granulocytic subtype dominating in gram-positive cases. J Leukoc Biol. 2014; 96: 685-93. doi: 10.1189/jlb.5HI0214-074R
129. Brandau S, Moses K, Lang S. The kinship of neutrophils and granulocytic myeloid-derived suppressor cells in cancer: cousins, siblings or twins? Semin Cancer Biol. 2013; 23: 171-82. doi: 10.1016/j.semcancer.2013.02.007
130. Hagerling C, Werb Z. Neutrophils: Critical components in experimental animal models of cancer. Semin Immunol. 2016 doi: 10.1016/j.smim.2016.02.003
131. Sippel TR, White J, Nag K, Tsvankin V, Klaassen M, Kleinschmidt-DeMasters BK, Waziri A. Neutrophil degranulation and immunosuppression in patients with GBM: restoration of cellular immune function by targeting arginase I. Clin Cancer Res. 2011; 17: 6992-7002. doi: 10.1158/1078-0432.CCR-11-1107
132. Arnardottir HH, Freysdottir J, Hardardottir I. Two circulating neutrophil populations in acute inflammation in mice. Inflamm Res. 2012; 61: 931-9. doi: 10.1007/s00011-012-0484-0
133. Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L, Worthen GS, Albelda SM. Polarization of tumorassociated neutrophil phenotype by TGF-beta: "N1" versus "N2" TAN. Cancer Cell. 2009; 16: 183-94. doi: 10.1016/j. ccr.2009.06.017
134. Pillay J, Kamp VM, van Hoffen E, Visser T, Tak T, Lammers JW, Ulfman LH, Leenen LP, Pickkers P, Koenderman L. A subset of neutrophils in human systemic inflammation inhibits T cell responses through Mac-1. J Clin Invest. 2012; 122: 327-36. doi: 10.1172/JCI57990
135. Sagiv JY, Michaeli J, Assi S, Mishalian I, Kisos H, Levy L, Damti P, Lumbroso D, Polyansky L, Sionov RV, Ariel A, Hovav AH, Henke E, et al. Phenotypic diversity and plasticity in circulating neutrophil subpopulations in cancer. Cell Rep. 2015; 10: 562-73. doi: 10.1016/j. celrep.2014.12.039
136. Singhal S, Bhojnagarwala PS, O'Brien S, Moon EK, Garfall AL, Rao AS, Quatromoni JG, Stephen TL, Litzky L, Deshpande C, Feldman MD, Hancock WW, Conejo-Garcia JR, 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. 2016; 30: 120-35. doi: 10.1016/j.ccell.2016.06.001
137. Brandau S, Dumitru CA, Lang S. Protumor and antitumor functions of neutrophil granulocytes. Semin Immunopathol. 2013; 35: 163-76. doi: 10.1007/s00281-012-0344-6
138. Lichtenstein A, Seelig M, Berek J, Zighelboim J. Human neutrophil-mediated lysis of ovarian cancer cells. Blood. 1989; 74: 805-9
139. Zivkovic M, Poljak-Blazi M, Zarkovic K, Mihaljevic D, Schaur RJ, Zarkovic N. Oxidative burst of neutrophils against melanoma B16-F10. Cancer Lett. 2007; 246: 100-8. doi: 10.1016/j.canlet.2006.02.002
140. Colotta F, Re F, Polentarutti N, Sozzani S, Mantovani A. Modulation of Granulocyte Survival and Programmed Cell-Death by Cytokines and Bacterial Products. Blood. 1992; 80: 2012-20
141. Fridlender ZG, Albelda SM. Tumor-associated neutrophils: friend or foe? Carcinogenesis. 2012; 33: 949-55. doi: 10.1093/carcin/bgs123
142. Granot Z, Fridlender ZG. Plasticity beyond cancer cells and the "immunosuppressive switch". Cancer Res. 2015; 75: 4441-5. doi: 10.1158/0008-5472.CAN-15-1502
143. Haley PJ. Species differences in the structure and function of the immune system. Toxicology. 2003; 188: 49-71