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Tumor-Induced Myeloid-Derived Suppressor Cells

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  • Authors: Francesco De Sanctis1, Vincenzo Bronte2, Stefano Ugel3
  • Editor: Siamon Gordon4
    Affiliations: 1: Immunology Section, Department of Pathology and Diagnostics, University of Verona, 37135, Verona, Italy; 2: Immunology Section, Department of Pathology and Diagnostics, University of Verona, 37135, Verona, Italy; 3: Immunology Section, Department of Pathology and Diagnostics, University of Verona, 37135, Verona, Italy; 4: Oxford University, Oxford, United Kingdom
  • Source: microbiolspec May 2016 vol. 4 no. 3 doi:10.1128/microbiolspec.MCHD-0016-2015
  • Received 29 July 2015 Accepted 14 August 2015 Published 06 May 2016
  • Vincenzo Bronte, [email protected]
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  • Abstract:

    Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous, immune-suppressive leukocyte population that develops systemically and infiltrates tumors. MDSCs can restrain the immune response through different mechanisms including essential metabolite consumption, reactive oxygen and nitrogen species production, as well as display of inhibitory surface molecules that alter T-cell trafficking and viability. Moreover, MDSCs play a role in tumor progression, acting directly on tumor cells and promoting cancer stemness, angiogenesis, stroma deposition, epithelial-to-mesenchymal transition, and metastasis formation. Many biological and pharmaceutical drugs affect MDSC expansion and functions in preclinical tumor models and patients, often reversing host immune dysfunctions and allowing a more effective tumor immunotherapy.

  • Citation: De Sanctis F, Bronte V, Ugel S. 2016. Tumor-Induced Myeloid-Derived Suppressor Cells. Microbiol Spectrum 4(3):MCHD-0016-2015. doi:10.1128/microbiolspec.MCHD-0016-2015.


1. Frank NY, Schatton T, Frank MH. 2010. The therapeutic promise of the cancer stem cell concept. J Clin Invest 120:41–50. [PubMed][CrossRef]
2. Balkwill F, Charles KA, Mantovani A. 2005. Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell 7:211–217. [PubMed][CrossRef]
3. Schreiber RD, Old LJ, Smyth MJ. 2011. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331:1565–1570. [PubMed][CrossRef]
4. Drake CG, Jaffee E, Pardoll DM. 2006. Mechanisms of immune evasion by tumors. Adv Immunol 90:51–81. [PubMed][CrossRef]
5. Rabinovich GA, Gabrilovich D, Sotomayor EM. 2007. Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol 25:267–296. [PubMed][CrossRef]
6. Chaux P, Favre N, Martin M, Martin F. 1997. Tumor-infiltrating dendritic cells are defective in their antigen-presenting function and inducible B7 expression in rats. Int J Cancer 72:619–624. [PubMed][CrossRef]
7. Geissmann F, Manz MG, Jung S, Sieweke MH, Merad M, Ley K. 2010. Development of monocytes, macrophages, and dendritic cells. Science 327:656–661. [PubMed][CrossRef]
8. Gabrilovich DI, Nagaraj S. 2009. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9:162–174. [PubMed][CrossRef]
9. Strober S. 1984. Natural suppressor (NS) cells, neonatal tolerance, and total lymphoid irradiation: exploring obscure relationships. Annu Rev Immunol 2:219–237. [PubMed][CrossRef]
10. Seung LP, Rowley DA, Dubey P, Schreiber H. 1995. Synergy between T-cell immunity and inhibition of paracrine stimulation causes tumor rejection. Proc Natl Acad Sci U S A 92:6254–6258. [PubMed][CrossRef]
11. Serafini P, Borrello I, Bronte V. 2006. Myeloid suppressor cells in cancer: recruitment, phenotype, properties, and mechanisms of immune suppression. Semin Cancer Biol 16:53–65. [PubMed][CrossRef]
12. Kusmartsev S, Gabrilovich DI. 2006. Role of immature myeloid cells in mechanisms of immune evasion in cancer. Cancer Immunol Immunother 55:237–245. [PubMed][CrossRef]
13. 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, Ramphal R, Gabrilovich DI, Reeves WH, Ayala A, Phillips J, Laface D, Heyworth PG, Clare-Salzler M, Moldawer LL. 2007. MyD88-dependent expansion of an immature GR-1 +CD11b + population induces T cell suppression and Th2 polarization in sepsis. J Exp Med 204:1463–1474. [PubMed][CrossRef]
14. Voisin MB, Buzoni-Gatel D, Bout D, Velge-Roussel F. 2004. Both expansion of regulatory GR1 + CD11b + myeloid cells and anergy of T lymphocytes participate in hyporesponsiveness of the lung-associated immune system during acute toxoplasmosis. Infect Immun 72:5487–5492. [PubMed][CrossRef]
15. Mencacci A, Montagnoli C, Bacci A, Cenci E, Pitzurra L, Spreca A, Kopf M, Sharpe AH, Romani L. 2002. CD80 +Gr-1 + myeloid cells inhibit development of antifungal Th1 immunity in mice with candidiasis. J Immunol 169:3180–3190. [PubMed][CrossRef]
16. Sunderkotter C, Nikolic T, Dillon MJ, Van Rooijen N, Stehling M, Drevets DA, Leenen PJ. 2004. Subpopulations of mouse blood monocytes differ in maturation stage and inflammatory response. J Immunol 172:4410–4417. [PubMed][CrossRef]
17. Haile LA, von Wasielewski R, Gamrekelashvili J, Kruger C, Bachmann O, Westendorf AM, Buer J, Liblau R, Manns MP, Korangy F, Greten TF. 2008. Myeloid-derived suppressor cells in inflammatory bowel disease: a new immunoregulatory pathway. Gastroenterology 135:871–881. [PubMed][CrossRef]
18. Makarenkova VP, Bansal V, Matta BM, Perez LA, Ochoa JB. 2006. CD11b +/Gr-1 + myeloid suppressor cells cause T cell dysfunction after traumatic stress. J Immunol 176:2085–2094. [PubMed][CrossRef]
19. Verschoor CP, Johnstone J, Millar J, Dorrington MG, Habibagahi M, Lelic A, Loeb M, Bramson JL, Bowdish DM. 2013. Blood CD33(+)HLA-DR(–) myeloid-derived suppressor cells are increased with age and a history of cancer. J Leukoc Biol 93:633–637. [PubMed][CrossRef]
20. Xiang X, Poliakov A, Liu C, Liu Y, Deng ZB, Wang J, Cheng Z, Shah SV, Wang GJ, Zhang L, Grizzle WE, Mobley J, Zhang HG. 2009. Induction of myeloid-derived suppressor cells by tumor exosomes. Int J Cancer 124:2621–2633. [PubMed][CrossRef]
21. Talmadge JE, Gabrilovich DI. 2013. History of myeloid-derived suppressor cells. Nat Rev Cancer 13:739–752. [PubMed][CrossRef]
22. 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; author reply 426. [PubMed][CrossRef]
23. 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, Cozzi E, Mandruzzato S, Bronte V. 2010. Tumor-induced tolerance and immune suppression depend on the C/EBPβ transcription factor. Immunity 32:790–802. [PubMed][CrossRef]
24. 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. 2010. Hierarchy of immunosuppressive strength among myeloid-derived suppressor cell subsets is determined by GM-CSF. Eur J Immunol 40:22–35. [PubMed][CrossRef]
25. Rossner S, Voigtlander C, Wiethe C, Hanig J, Seifarth C, Lutz MB. 2005. Myeloid dendritic cell precursors generated from bone marrow suppress T cell responses via cell contact and nitric oxide production in vitro. Eur J Immunol 35:3533–3544. [PubMed][CrossRef]
26. Kusmartsev S, Gabrilovich DI. 2006. Effect of tumor-derived cytokines and growth factors on differentiation and immune suppressive features of myeloid cells in cancer. Cancer Metastasis Rev 25:323–331. [PubMed][CrossRef]
27. Kusmartsev S, Cheng F, Yu B, Nefedova Y, Sotomayor E, Lush R, Gabrilovich D. 2003. All- trans-retinoic acid eliminates immature myeloid cells from tumor-bearing mice and improves the effect of vaccination. Cancer Res 63:4441–4449. [PubMed]
28. Ugel S, Peranzoni E, Desantis G, Chioda M, Walter S, Weinschenk T, Ochando JC, Cabrelle A, Mandruzzato S, Bronte V. 2012. Immune tolerance to tumor antigens occurs in a specialized environment of the spleen. Cell Rep 2:628–639. [PubMed][CrossRef]
29. Kusmartsev S, Gabrilovich DI. 2003. Inhibition of myeloid cell differentiation in cancer: the role of reactive oxygen species. J Leukoc Biol 74:186–196. [PubMed][CrossRef]
30. Auffray C, Sieweke MH, Geissmann F. 2009. Blood monocytes: development, heterogeneity, and relationship with dendritic cells. Annu Rev Immunol 27:669–692. [PubMed][CrossRef]
31. Movahedi K, Guilliams M, Van den Bossche J, Van den Bergh R, Gysemans C, Beschin A, De Baetselier P, Van Ginderachter JA. 2008. Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity. Blood 111:4233–4244. [PubMed][CrossRef]
32. Youn JI, Nagaraj S, Collazo M, Gabrilovich DI. 2008. Subsets of myeloid-derived suppressor cells in tumor-bearing mice. J Immunol 181:5791–5802. [PubMed][CrossRef]
33. Haile LA, Gamrekelashvili J, Manns MP, Korangy F, Greten TF. 2010. CD49d is a new marker for distinct myeloid-derived suppressor cell subpopulations in mice. J Immunol 185:203–210. [PubMed][CrossRef]
34. Gabrilovich DI, Ostrand-Rosenberg S, Bronte V. 2012. Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol 12:253–268. [PubMed][CrossRef]
35. Youn JI, Kumar V, Collazo M, Nefedova Y, Condamine T, Cheng P, Villagra A, Antonia S, McCaffrey JC, Fishman M, Sarnaik A, Horna P, Sotomayor E, Gabrilovich DI. 2013. Epigenetic silencing of retinoblastoma gene regulates pathologic differentiation of myeloid cells in cancer. Nat Immunol 14:211–220. [PubMed][CrossRef]
36. Gallina G, Dolcetti L, Serafini P, De Santo C, Marigo I, Colombo MP, Basso G, Brombacher F, Borrello I, Zanovello P, Bicciato S, Bronte V. 2006. Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8 + T cells. J Clin Invest 116:2777–2790. [PubMed][CrossRef]
37. Roth F, De La Fuente AC, Vella JL, Zoso A, Inverardi L, Serafini P. 2012. Aptamer-mediated blockade of IL4Rα triggers apoptosis of MDSCs and limits tumor progression. Cancer Res 72:1373–1383. [PubMed][CrossRef]
38. Galli SJ, Borregaard N, Wynn TA. 2011. Phenotypic and functional plasticity of cells of innate immunity: macrophages, mast cells and neutrophils. Nat Immunol 12:1035–1044. [PubMed][CrossRef]
39. Peranzoni E, Zilio S, Marigo I, Dolcetti L, Zanovello P, Mandruzzato S, Bronte V. 2010. Myeloid-derived suppressor cell heterogeneity and subset definition. Curr Opin Immunol 22:238–244. [PubMed][CrossRef]
40. Biswas SK, Mantovani A. 2010. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol 11:889–896. [PubMed][CrossRef]
41. Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, Goerdt S, Gordon S, Hamilton JA, Ivashkiv LB, Lawrence T, Locati M, Mantovani A, Martinez FO, Mege JL, Mosser DM, Natoli G, Saeij JP, Schultze JL, Shirey KA, Sica A, Suttles J, Udalova I, van Ginderachter JA, Vogel SN, Wynn TA. 2014. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41:14–20. [PubMed][CrossRef]
42. Umemura N, Saio M, Suwa T, Kitoh Y, Bai J, Nonaka K, Ouyang GF, Okada M, Balazs M, Adany R, Shibata T, Takami T. 2008. Tumor-infiltrating myeloid-derived suppressor cells are pleiotropic-inflamed monocytes/macrophages that bear M1- and M2-type characteristics. J Leukoc Biol 83:1136–1144. [PubMed][CrossRef]
43. Movahedi K, Laoui D, Gysemans C, Baeten M, Stangé G, Van den Bossche J, Mack M, Pipeleers D, In’t Veld P, De Baetselier P, Van Ginderachter JA. 2010. Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. Cancer Res 70:5728–5739. [PubMed][CrossRef]
44. Wynn TA, Chawla A, Pollard JW. 2013. Macrophage biology in development, homeostasis and disease. Nature 496:445–455. [PubMed][CrossRef]
45. Colegio OR, Chu NQ, Szabo AL, Chu T, Rhebergen AM, Jairam V, Cyrus N, Brokowski CE, Eisenbarth SC, Phillips GM, Cline GW, Phillips AJ, Medzhitov R. 2014. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513:559–563. [PubMed][CrossRef]
46. Kobayashi Y. 2008. The role of chemokines in neutrophil biology. Front Biosci 13:2400–2407. [PubMed][CrossRef]
47. 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-β: “N1” versus “N2” TAN. Cancer Cell 16:183–194. [PubMed][CrossRef]
48. 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. [PubMed][CrossRef]
49. 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. [PubMed][CrossRef]
50. 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. doi:10.1371/journal.pone.0031524. [PubMed][CrossRef]
51. Köffel R, Meshcheryakova A, Warszawska J, Hennig A, Wagner K, Jörgl A, Gubi D, Moser D, Hladik A, Hoffmann U, Fischer MB, van den Berg W, Koenders M, Scheinecker C, Gesslbauer B, Knapp S, Strobl H. 2014. Monocytic cell differentiation from band-stage neutrophils under inflammatory conditions via MKK6 activation. Blood 124:2713–2724. [PubMed][CrossRef]
52. Zoso A, Mazza EM, Bicciato S, Mandruzzato S, Bronte V, Serafini P, Inverardi L. 2014. Human fibrocytic myeloid-derived suppressor cells express IDO and promote tolerance via Treg-cell expansion. Eur J Immunol 44:3307–3319. [PubMed][CrossRef]
53. Zhang H, Maric I, DiPrima MJ, Khan J, Orentas RJ, Kaplan RN, Mackall CL. 2013. Fibrocytes represent a novel MDSC subset circulating in patients with metastatic cancer. Blood 122:1105–1113. [PubMed][CrossRef]
54. Shi Y, Ou L, Han S, Li M, Pena MM, Pena EA, Liu C, Nagarkatti M, Fan D, Ai W. 2014. Deficiency of Kruppel-like factor KLF4 in myeloid-derived suppressor cells inhibits tumor pulmonary metastasis in mice accompanied by decreased fibrocytes. Oncogenesis 3:e129. doi:10.1038/oncsis.2014.44. [PubMed][CrossRef]
55. Park YJ, Song B, Kim YS, Kim EK, Lee JM, Lee GE, Kim JO, Kim YJ, Chang WS, Kang CY. 2013. Tumor microenvironmental conversion of natural killer cells into myeloid-derived suppressor cells. Cancer Res 73:5669–5681. [PubMed][CrossRef]
56. Diaz-Montero CM, Salem ML, Nishimura MI, Garrett-Mayer E, Cole DJ, Montero AJ. 2009. Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol Immunother 58:49–59. [PubMed][CrossRef]
57. 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][CrossRef]
58. Rodriguez PC, Ernstoff MS, Hernandez C, Atkins M, Zabaleta J, Sierra R, Ochoa AC. 2009. Arginase I-producing myeloid-derived suppressor cells in renal cell carcinoma are a subpopulation of activated granulocytes. Cancer Res 69:1553–1560. [PubMed][CrossRef]
59. Gabitass RF, Annels NE, Stocken DD, Pandha HA, Middleton GW. 2011. 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 60:1419–1430. [PubMed][CrossRef]
60. Eruslanov E, Neuberger M, Daurkin I, Perrin GQ, Algood C, Dahm P, Rosser C, Vieweg J, Gilbert SM, Kusmartsev S. 2012. Circulating and tumor-infiltrating myeloid cell subsets in patients with bladder cancer. Int J Cancer 130:1109–1119. [PubMed][CrossRef]
61. Solito S, Marigo I, Pinton L, Damuzzo V, Mandruzzato S, Bronte V. 2014. Myeloid-derived suppressor cell heterogeneity in human cancers. Ann N Y Acad Sci 1319:47–65. [PubMed][CrossRef]
62. Pak AS, Wright MA, Matthews JP, Collins SL, Petruzzelli GJ, Young MR. 1995. 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 1:95–103. [PubMed]
63. 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. [PubMed][CrossRef]
64. 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, Mahr A, Maurer D, Vass V, Trautwein C, Lewandrowski P, Flohr C, Pohla H, Stanczak JJ, Bronte V, Mandruzzato S, Biedermann T, Pawelec G, Derhovanessian E, Yamagishi H, Miki T, Hongo F, Takaha N, Hirakawa K, Tanaka H, Stevanovic S, Frisch J, Mayer-Mokler A, Kirner A, Rammensee HG, Reinhardt C, Singh-Jasuja H. 2012. Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival. Nat Med 18:1254–1261. [PubMed][CrossRef]
65. 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. [PubMed][CrossRef]
66. Trellakis S, Bruderek K, Hutte J, Elian M, Hoffmann TK, Lang S, Brandau S. 2013. Granulocytic myeloid-derived suppressor cells are cryosensitive and their frequency does not correlate with serum concentrations of colony-stimulating factors in head and neck cancer. Innate Immun 19:328–336. [PubMed][CrossRef]
67. 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. 2005. Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: a mechanism of tumor evasion. Cancer Res 65:3044–3048. [PubMed]
68. Idorn M, Kollgaard T, Kongsted P, Sengelov L, Thor Straten P. 2014. Correlation between frequencies of blood monocytic myeloid-derived suppressor cells, regulatory T cells and negative prognostic markers in patients with castration-resistant metastatic prostate cancer. Cancer Immunol Immunother 63:1177–1187. [PubMed][CrossRef]
69. Gao J, Wu Y, Su Z, Amoah Barnie P, Jiao Z, Bie Q, Lu L, Wang S, Xu H. 2014. Infiltration of alternatively activated macrophages in cancer tissue is associated with MDSC and Th2 polarization in patients with esophageal cancer. PLoS One 9:e104453. doi:10.1371/journal.pone.0104453. [PubMed][CrossRef]
70. Markowitz J, Brooks TR, Duggan MC, Paul BK, Pan X, Wei L, Abrams Z, Luedke E, Lesinski GB, Mundy-Bosse B, Bekaii-Saab T, Carson WE, III. 2014. Patients with pancreatic adenocarcinoma exhibit elevated levels of myeloid-derived suppressor cells upon progression of disease. Cancer Immunol Immunother 64:149–159. [PubMed][CrossRef]
71. Rudolph BM, Loquai C, Gerwe A, Bacher N, Steinbrink K, Grabbe S, Tuettenberg A. 2014. Increased frequencies of CD11b +CD33 +CD14 +HLA-DR low myeloid-derived suppressor cells are an early event in melanoma patients. Exp Dermatol 23:202–204. [PubMed][CrossRef]
72. Weide B, Martens A, Zelba H, Stutz C, Derhovanessian E, Di Giacomo AM, Maio M, Sucker A, Schilling B, Schadendorf D, Büttner P, Garbe C, Pawelec G. 2014. Myeloid-derived suppressor cells predict survival of patients with advanced melanoma: comparison with regulatory T cells and NY-ESO-1- or melan-A-specific T cells. Clin Cancer Res 20:1601–1609. [PubMed][CrossRef]
73. Roca H, Varsos ZS, Sud S, Craig MJ, Ying C, Pienta KJ. 2009. CCL2 and interleukin-6 promote survival of human CD11b + peripheral blood mononuclear cells and induce M2-type macrophage polarization. J Biol Chem 284:34342–34354. [PubMed][CrossRef]
74. Nagaraj S, Gabrilovich DI. 2008. Tumor escape mechanism governed by myeloid-derived suppressor cells. Cancer Res 68:2561–2563. [PubMed][CrossRef]
75. Srivastava MK, Sinha P, Clements VK, Rodriguez P, Ostrand-Rosenberg S. 2010. Myeloid-derived suppressor cells inhibit T-cell activation by depleting cystine and cysteine. Cancer Res 70:68–77. [PubMed][CrossRef]
76. Munn DH, Sharma MD, Baban B, Harding HP, Zhang Y, Ron D, Mellor AL. 2005. GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity 22:633–642. [PubMed][CrossRef]
77. Quintana FJ, Murugaiyan G, Farez MF, Mitsdoerffer M, Tukpah AM, Burns EJ, Weiner HL. 2010. An endogenous aryl hydrocarbon receptor ligand acts on dendritic cells and T cells to suppress experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 107:20768–20773. [PubMed][CrossRef]
78. Rolinski J, Hus I. 2014. Breaking immunotolerance of tumors: a new perspective for dendritic cell therapy. J Immunotoxicol 11:311–318. [PubMed][CrossRef]
79. Godin-Ethier J, Hanafi LA, Piccirillo CA, Lapointe R. 2011. Indoleamine 2,3-dioxygenase expression in human cancers: clinical and immunologic perspectives. Clin Cancer Res 17:6985–6991. [PubMed][CrossRef]
80. Bronte V, Zanovello P. 2005. Regulation of immune responses by l-arginine metabolism. Nat Rev Immunol 5:641–654. [PubMed][CrossRef]
81. Mazzoni A, Bronte V, Visintin A, Spitzer JH, Apolloni E, Serafini P, Zanovello P, Segal DM. 2002. Myeloid suppressor lines inhibit T cell responses by an NO-dependent mechanism. J Immunol 168:689–695. [PubMed][CrossRef]
82. Macphail SE, Gibney CA, Brooks BM, Booth CG, Flanagan BF, Coleman JW. 2003. Nitric oxide regulation of human peripheral blood mononuclear cells: critical time dependence and selectivity for cytokine versus chemokine expression. J Immunol 171:4809–4815. [PubMed][CrossRef]
83. Baniyash M. 2004. TCR ζ-chain downregulation: curtailing an excessive inflammatory immune response. Nat Rev Immunol 4:675–687. [PubMed][CrossRef]
84. Rodriguez PC, Quiceno DG, Ochoa AC. 2007. l-Arginine availability regulates T-lymphocyte cell-cycle progression. Blood 109:1568–1573. [PubMed][CrossRef]
85. Rodriguez PC, Hernandez CP, Morrow K, Sierra R, Zabaleta J, Wyczechowska DD, Ochoa AC. 2010. l-Arginine deprivation regulates cyclin D3 mRNA stability in human T cells by controlling HuR expression. J Immunol 185:5198–5204. [PubMed][CrossRef]
86. Raber P, Ochoa AC, Rodriguez PC. 2012. Metabolism of l-arginine by myeloid-derived suppressor cells in cancer: mechanisms of T cell suppression and therapeutic perspectives. Immunol Invest 41:614–634. [PubMed][CrossRef]
87. Bedard K, Krause KH. 2007. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87:245–313. [PubMed][CrossRef]
88. Raad H, Paclet MH, Boussetta T, Kroviarski Y, Morel F, Quinn MT, Gougerot-Pocidalo MA, Dang PM, El-Benna J. 2009. Regulation of the phagocyte NADPH oxidase activity: phosphorylation of gp91 phox/NOX2 by protein kinase C enhances its diaphorase activity and binding to Rac2, p67 phox, and p47 phox. FASEB J 23:1011–1022. [PubMed][CrossRef]
89. Schmielau J, Nalesnik MA, Finn OJ. 2001. Suppressed T-cell receptor zeta chain expression and cytokine production in pancreatic cancer patients. Clin Cancer Res 7(3 Suppl) :933s–939s. [PubMed]
90. Otsuji M, Kimura Y, Aoe T, Okamoto Y, Saito T. 1996. Oxidative stress by tumor-derived macrophages suppresses the expression of CD3 ζ chain of T-cell receptor complex and antigen-specific T-cell responses. Proc Natl Acad Sci U S A 93:13119–13124. [PubMed][CrossRef]
91. Alvarez B, Radi R. 2003. Peroxynitrite reactivity with amino acids and proteins. Amino Acids 25:295–311. [PubMed][CrossRef]
92. Hardy LL, Wick DA, Webb JR. 2008. Conversion of tyrosine to the inflammation-associated analog 3′-nitrotyrosine at either TCR- or MHC-contact positions can profoundly affect recognition of the MHC class I-restricted epitope of lymphocytic choriomeningitis virus glycoprotein 33 by CD8 T cells. J Immunol 180:5956–5962. [PubMed][CrossRef]
93. Nagaraj S, Schrum AG, Cho HI, Celis E, Gabrilovich DI. 2010. Mechanism of T cell tolerance induced by myeloid-derived suppressor cells. J Immunol 184:3106–3116. [PubMed][CrossRef]
94. De Sanctis F, Sandri S, Ferrarini G, Pagliarello I, Sartoris S, Ugel S, Marigo I, Molon B, Bronte V. 2014. The emerging immunological role of post-translational modifications by reactive nitrogen species in cancer microenvironment. Front Immunol 5:69. doi:10.3389/fimmu.2014.00069. [PubMed][CrossRef]
95. Hanson EM, Clements VK, Sinha P, Ilkovitch D, Ostrand-Rosenberg S. 2009. Myeloid-derived suppressor cells down-regulate L-selectin expression on CD4 + and CD8 + T cells. J Immunol 183:937–944. [PubMed][CrossRef]
96. Molon B, Ugel S, Del Pozzo F, Soldani C, Zilio S, Avella D, De Palma A, Mauri P, Monegal A, Rescigno M, Savino B, Colombo P, Jonjic N, Pecanic S, Lazzarato L, Fruttero R, Gasco A, Bronte V, Viola A. 2011. Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells. J Exp Med 208:1949–1962. [PubMed][CrossRef]
97. Elkabets M, Ribeiro VS, Dinarello CA, Ostrand-Rosenberg S, Di Santo JP, Apte RN, Vosshenrich CA. 2010. IL-1β regulates a novel myeloid-derived suppressor cell subset that impairs NK cell development and function. Eur J Immunol 40:3347–3357. [PubMed][CrossRef]
98. Wolfraim LA, Walz TM, James Z, Fernandez T, Letterio JJ. 2004. p21 Cip1 and p27 Kip1 act in synergy to alter the sensitivity of naive T cells to TGF-β-mediated G 1 arrest through modulation of IL-2 responsiveness. J Immunol 173:3093–3102. [PubMed][CrossRef]
99. Brabletz T, Pfeuffer I, Schorr E, Siebelt F, Wirth T, Serfling E. 1993. Transforming growth factor β and cyclosporin A inhibit the inducible activity of the interleukin-2 gene in T cells through a noncanonical octamer-binding site. Mol Cell Biol 13:1155–1162. [PubMed][CrossRef]
100. Becker C, Fantini MC, Neurath MF. 2006. TGF-β as a T cell regulator in colitis and colon cancer. Cytokine Growth Factor Rev 17:97–106. [PubMed][CrossRef]
101. Serafini P, Mgebroff S, Noonan K, Borrello I. 2008. Myeloid-derived suppressor cells promote cross-tolerance in B-cell lymphoma by expanding regulatory T cells. Cancer Res 68:5439–5449. [PubMed][CrossRef]
102. Hoechst B, Gamrekelashvili J, Manns MP, Greten TF, Korangy F. 2011. Plasticity of human Th17 cells and iTregs is orchestrated by different subsets of myeloid cells. Blood 117:6532–6541. [PubMed][CrossRef]
103. Sinha P, Clements VK, Bunt SK, Albelda SM, Ostrand-Rosenberg S. 2007. Cross-talk between myeloid-derived suppressor cells and macrophages subverts tumor immunity toward a type 2 response. J Immunol 179:977–983. [PubMed][CrossRef]
104. Li H, Collado M, Villasante A, Strati K, Ortega S, Cañamero M, Blasco MA, Serrano M. 2009. The Ink4/Arf locus is a barrier for iPS cell reprogramming. Nature 460:1136–1139. [PubMed][CrossRef]
105. Chen Z, Trotman LC, Shaffer D, Lin HK, Dotan ZA, Niki M, Koutcher JA, Scher HI, Ludwig T, Gerald W, Cordon-Cardo C, Pandolfi PP. 2005. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436:725–730. [PubMed][CrossRef]
106. Collado M, Gil J, Efeyan A, Guerra C, Schuhmacher AJ, Barradas M, Benguria A, Zaballos A, Flores JM, Barbacid M, Beach D, Serrano M. 2005. Tumour biology: senescence in premalignant tumours. Nature 436:642. [PubMed][CrossRef]
107. Di Mitri D, Toso A, Chen JJ, Sarti M, Pinton S, Jost TR, D’Antuono R, Montani E, Garcia-Escudero R, Guccini I, Da Silva-Alvarez S, Collado M, Eisenberger M, Zhang Z, Catapano C, Grassi F, Alimonti A. 2014. Tumour-infiltrating Gr-1 + myeloid cells antagonize senescence in cancer. Nature 515:134–137. [PubMed][CrossRef]
108. Cui TX, Kryczek I, Zhao L, Zhao E, Kuick R, Roh MH, Vatan L, Szeliga W, Mao Y, Thomas DG, Kotarski J, Tarkowski R, Wicha M, Cho K, Giordano T, Liu R, Zou W. 2013. Myeloid-derived suppressor cells enhance stemness of cancer cells by inducing microRNA101 and suppressing the corepressor CtBP2. Immunity 39:611–621. [PubMed][CrossRef]
109. Panni RZ, Sanford DE, Belt BA, Mitchem JB, Worley LA, Goetz BD, Mukherjee P, Wang-Gillam A, Link DC, Denardo DG, Goedegebuure SP, Linehan DC. 2014. Tumor-induced STAT3 activation in monocytic myeloid-derived suppressor cells enhances stemness and mesenchymal properties in human pancreatic cancer. Cancer Immunol Immunother 63:513–528. [PubMed][CrossRef]
110. Ostrand-Rosenberg S, Sinha P. 2009. Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol 182:4499–4506. [PubMed][CrossRef]
111. Doedens AL, Stockmann C, Rubinstein MP, Liao D, Zhang N, DeNardo DG, Coussens LM, Karin M, Goldrath AW, Johnson RS. 2010. Macrophage expression of hypoxia-inducible factor-1α suppresses T-cell function and promotes tumor progression. Cancer Res 70:7465–7475. [PubMed][CrossRef]
112. Yang L, DeBusk LM, Fukuda K, Fingleton B, Green-Jarvis B, Shyr Y, Matrisian LM, Carbone DP, Lin PC. 2004. Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell 6:409–421. [PubMed][CrossRef]
113. Shojaei F, Wu X, Malik AK, Zhong C, Baldwin ME, Schanz S, Fuh G, Gerber HP, Ferrara N. 2007. Tumor refractoriness to anti-VEGF treatment is mediated by CD11b +Gr1 + myeloid cells. Nat Biotechnol 25:911–920. [PubMed][CrossRef]
114. Finke J, Ko J, Rini B, Rayman P, Ireland J, Cohen P. 2011. MDSC as a mechanism of tumor escape from sunitinib mediated anti-angiogenic therapy. Int Immunopharmacol 11:856–861. [PubMed][CrossRef]
115. Sceneay J, Chow MT, Chen A, Halse HM, Wong CS, Andrews DM, Sloan EK, Parker BS, Bowtell DD, Smyth MJ, Möller A. 2012. Primary tumor hypoxia recruits CD11b +/Ly6C med/Ly6G + immune suppressor cells and compromises NK cell cytotoxicity in the premetastatic niche. Cancer Res 72:3906–3911. [PubMed][CrossRef]
116. Shojaei F, Wu X, Zhong C, Yu L, Liang XH, Yao J, Blanchard D, Bais C, Peale FV, van Bruggen N, Ho C, Ross J, Tan M, Carano RA, Meng YG, Ferrara N. 2007. Bv8 regulates myeloid-cell-dependent tumour angiogenesis. Nature 450:825–831. [PubMed][CrossRef]
117. Sinha P, Okoro C, Foell D, Freeze HH, Ostrand-Rosenberg S, Srikrishna G. 2008. Proinflammatory S100 proteins regulate the accumulation of myeloid-derived suppressor cells. J Immunol 181:4666–4675. [PubMed][CrossRef]
118. Hiratsuka S, Watanabe A, Sakurai Y, Akashi-Takamura S, Ishibashi S, Miyake K, Shibuya M, Akira S, Aburatani H, Maru Y. 2008. The S100A8-serum amyloid A3-TLR4 paracrine cascade establishes a pre-metastatic phase. Nat Cell Biol 10:1349–1355. [PubMed][CrossRef]
119. Oh K, Lee OY, Shon SY, Nam O, Ryu PM, Seo MW, Lee DS. 2013. A mutual activation loop between breast cancer cells and myeloid-derived suppressor cells facilitates spontaneous metastasis through IL-6 trans-signaling in a murine model. Breast Cancer Res 15:R79. doi:10.1186/bcr3473. [CrossRef]
120. Hiratsuka S, Watanabe A, Aburatani H, Maru Y. 2006. Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis. Nat Cell Biol 8:1369–1375. [PubMed][CrossRef]
121. Toh B, Wang X, Keeble J, Sim WJ, Khoo K, Wong WC, Kato M, Prevost-Blondel A, Thiery JP, Abastado JP. 2011. Mesenchymal transition and dissemination of cancer cells is driven by myeloid-derived suppressor cells infiltrating the primary tumor. PLoS Biol 9:e1001162. doi:10.1371/journal.pbio.1001162. [PubMed][CrossRef]
122. Zhu L, Li X, Chen Y, Fang J, Ge Z. 2015. High-mobility group box 1: a novel inducer of the epithelial-mesenchymal transition in colorectal carcinoma. Cancer Lett 357:527–534. [PubMed][CrossRef]
123. Gao D, Joshi N, Choi H, Ryu S, Hahn M, Catena R, Sadik H, Argani P, Wagner P, Vahdat LT, Port JL, Stiles B, Sukumar S, Altorki NK, Rafii S, Mittal V. 2012. Myeloid progenitor cells in the premetastatic lung promote metastases by inducing mesenchymal to epithelial transition. Cancer Res 72:1384–1394. [PubMed][CrossRef]
124. Catena R, Bhattacharya N, El Rayes T, Wang S, Choi H, Gao D, Ryu S, Joshi N, Bielenberg D, Lee SB, Haukaas SA, Gravdal K, Halvorsen OJ, Akslen LA, Watnick RS, Mittal V. 2013. Bone marrow-derived Gr1 + cells can generate a metastasis-resistant microenvironment via induced secretion of thrombospondin-1. Cancer Discov 3:578–589. [PubMed][CrossRef]
125. Nakamura I, Shibata M, Gonda K, Yazawa T, Shimura T, Anazawa T, Suzuki S, Sakurai K, Koyama Y, Ohto H, Tomita R, Gotoh M, Takenoshita S. 2013. Serum levels of vascular endothelial growth factor are increased and correlate with malnutrition, immunosuppression involving MDSCs and systemic inflammation in patients with cancer of the digestive system. Oncol Lett 5:1682–1686. [PubMed]
126. Cuenca AG, Cuenca AL, Winfield RD, Joiner DN, Gentile L, Delano MJ, Kelly-Scumpia KM, Scumpia PO, Matheny MK, Scarpace PJ, Vila L, Efron PA, LaFace DM, Moldawer LL. 2014. Novel role for tumor-induced expansion of myeloid-derived cells in cancer cachexia. J Immunol 192:6111–6119. [PubMed][CrossRef]
127. Gerharz CD, Reinecke P, Schneider EM, Schmitz M, Gabbert HE. 2001. Secretion of GM-CSF and M-CSF by human renal cell carcinomas of different histologic types. Urology 58:821–827. [PubMed][CrossRef]
128. Lin EY, Gouon-Evans V, Nguyen AV, Pollard JW. 2002. The macrophage growth factor CSF-1 in mammary gland development and tumor progression. J Mammary Gland Biol Neoplasia 7:147–162. [PubMed][CrossRef]
129. Priceman SJ, Sung JL, Shaposhnik Z, Burton JB, Torres-Collado AX, Moughon DL, Johnson M, Lusis AJ, Cohen DA, Iruela-Arispe ML, Wu L. 2010. Targeting distinct tumor-infiltrating myeloid cells by inhibiting CSF-1 receptor: combating tumor evasion of antiangiogenic therapy. Blood 115:1461–1471. [PubMed][CrossRef]
130. 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. [PubMed][CrossRef]
131. Clark CE, Hingorani SR, Mick R, Combs C, Tuveson DA, Vonderheide RH. 2007. Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res 67:9518–9527. [PubMed][CrossRef]
132. Bayne LJ, Beatty GL, Jhala N, Clark CE, Rhim AD, Stanger BZ, Vonderheide RH. 2012. Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer. Cancer Cell 21:822–835. [PubMed][CrossRef]
133. Lesina M, Kurkowski MU, Ludes K, Rose-John S, Treiber M, Klöppel G, Yoshimura A, Reindl W, Sipos B, Akira S, Schmid RM, Algül H. 2011. Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell 19:456–469. [PubMed][CrossRef]
134. Serafini P, Carbley R, Noonan KA, Tan G, Bronte V, Borrello I. 2004. High-dose granulocyte-macrophage colony-stimulating factor-producing vaccines impair the immune response through the recruitment of myeloid suppressor cells. Cancer Res 64:6337–6343. [PubMed][CrossRef]
135. Parmiani G, Castelli C, Pilla L, Santinami M, Colombo MP, Rivoltini L. 2007. Opposite immune functions of GM-CSF administered as vaccine adjuvant in cancer patients. Ann Oncol 18:226–232. [PubMed][CrossRef]
136. Trikha M, Corringham R, Klein B, Rossi JF. 2003. Targeted anti-interleukin-6 monoclonal antibody therapy for cancer: a review of the rationale and clinical evidence. Clin Cancer Res 9:4653–4665. [PubMed]
137. Terabe M, Matsui S, Noben-Trauth N, Chen H, Watson C, Donaldson DD, Carbone DP, Paul WE, Berzofsky JA. 2000. NKT cell-mediated repression of tumor immunosurveillance by IL-13 and the IL-4R-STAT6 pathway. Nat Immunol 1:515–520. [PubMed][CrossRef]
138. Bronte V, Serafini P, De Santo C, Marigo I, Tosello V, Mazzoni A, Segal DM, Staib C, Lowel M, Sutter G, Colombo MP, Zanovello P. 2003. IL-4-induced arginase 1 suppresses alloreactive T cells in tumor-bearing mice. J Immunol 170:270–278. [PubMed][CrossRef]
139. Cheng P, Corzo CA, Luetteke N, Yu B, Nagaraj S, Bui MM, Ortiz M, Nacken W, Sorg C, Vogl T, Roth J, Gabrilovich DI. 2008. Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein. J Exp Med 205:2235–2249. [PubMed][CrossRef]
140. Parker KH, Sinha P, Horn LA, Clements VK, Yang H, Li J, Tracey KJ, Ostrand-Rosenberg S. 2014. HMGB1 enhances immune suppression by facilitating the differentiation and suppressive activity of myeloid-derived suppressor cells. Cancer Res 74:5723–5733. [PubMed][CrossRef]
141. Kim EK, Jeon I, Seo H, Park YJ, Song B, Lee KA, Jang Y, Chung Y, Kang CY. 2014. Tumor-derived osteopontin suppresses antitumor immunity by promoting extramedullary myelopoiesis. Cancer Res 74:6705–6716. [PubMed][CrossRef]
142. Sangaletti S, Tripodo C, Sandri S, Torselli I, Vitali C, Ratti C, Botti L, Burocchi A, Porcasi R, Tomirotti A, Colombo MP, Chiodoni C. 2014. Osteopontin shapes immunosuppression in the metastatic niche. Cancer Res 74:4706–4719. [PubMed][CrossRef]
143. Yoshimura A. 2006. Signal transduction of inflammatory cytokines and tumor development. Cancer Sci 97:439–447. [PubMed][CrossRef]
144. Kusmartsev S, Gabrilovich DI. 2005. STAT1 signaling regulates tumor-associated macrophage-mediated T cell deletion. J Immunol 174:4880–4891. [PubMed][CrossRef]
145. Beatty GL, Paterson Y. 2000. IFN-γ can promote tumor evasion of the immune system in vivo by down-regulating cellular levels of an endogenous tumor antigen. J Immunol 165:5502–5508. [PubMed][CrossRef]
146. Lehtonen A, Matikainen S, Miettinen M, Julkunen I. 2002. Granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced STAT5 activation and target-gene expression during human monocyte/macrophage differentiation. J Leukoc Biol 71:511–519. [PubMed]
147. Waight JD, Netherby C, Hensen ML, Miller A, Hu Q, Liu S, Bogner PN, Farren MR, Lee KP, Liu K, Abrams SI. 2013. Myeloid-derived suppressor cell development is regulated by a STAT/IRF-8 axis. J Clin Invest 123:4464–4478. [PubMed][CrossRef]
148. Xin H, Zhang C, Herrmann A, Du Y, Figlin R, Yu H. 2009. Sunitinib inhibition of Stat3 induces renal cell carcinoma tumor cell apoptosis and reduces immunosuppressive cells. Cancer Res 69:2506–2513. [PubMed][CrossRef]
149. Cohen PA, Ko JS, Storkus WJ, Spencer CD, Bradley JM, Gorman JE, McCurry DB, Zorro-Manrique S, Dominguez AL, Pathangey LB, Rayman PA, Rini BI, Gendler SJ, Finke JH. 2012. Myeloid-derived suppressor cells adhere to physiologic STAT3- vs STAT5-dependent hematopoietic programming, establishing diverse tumor-mediated mechanisms of immunologic escape. Immunol Invest 41:680–710. [PubMed][CrossRef]
150. Ostrand-Rosenberg S, Clements VK, Terabe M, Park JM, Berzofsky JA, Dissanayake SK. 2002. Resistance to metastatic disease in STAT6-deficient mice requires hemopoietic and nonhemopoietic cells and is IFN-γ dependent. J Immunol 169:5796–5804. [PubMed][CrossRef]
151. Munera V, Popovic PJ, Bryk J, Pribis J, Caba D, Matta BM, Zenati M, Ochoa JB. 2010. Stat 6-dependent induction of myeloid derived suppressor cells after physical injury regulates nitric oxide response to endotoxin. Ann Surg 251:120–126. [PubMed][CrossRef]
152. Corzo CA, Cotter MJ, Cheng P, Cheng F, Kusmartsev S, Sotomayor E, Padhya T, McCaffrey TV, McCaffrey JC, Gabrilovich DI. 2009. Mechanism regulating reactive oxygen species in tumor-induced myeloid-derived suppressor cells. J Immunol 182:5693–5701. [PubMed][CrossRef]
153. Sander LE, Sackett SD, Dierssen U, Beraza N, Linke RP, Muller M, Blander JM, Tacke F, Trautwein C. 2010. Hepatic acute-phase proteins control innate immune responses during infection by promoting myeloid-derived suppressor cell function. J Exp Med 207:1453–1464. [PubMed][CrossRef]
154. 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, Martin F, Chauffert B, Solary E, Zitvogel L, Garrido C, Ryffel B, Borg C, Apetoh L, Rébé C, Ghiringhelli F. 2010. Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells. J Clin Invest 120:457–471. [CrossRef]
155. Zhang H, Nguyen-Jackson H, Panopoulos AD, Li HS, Murray PJ, Watowich SS. 2010. STAT3 controls myeloid progenitor growth during emergency granulopoiesis. Blood 116:2462–2471. [PubMed][CrossRef]
156. Natsuka S, Akira S, Nishio Y, Hashimoto S, Sugita T, Isshiki H, Kishimoto T. 1992. Macrophage differentiation-specific expression of NF-IL6, a transcription factor for interleukin-6. Blood 79:460–466. [PubMed]
157. van Dijk TB, Baltus B, Raaijmakers JA, Lammers JW, Koenderman L, de Groot RP. 1999. A composite C/EBP binding site is essential for the activity of the promoter of the IL-3/IL-5/granulocyte-macrophage colony-stimulating factor receptor βc gene. J Immunol 163:2674–2680. [PubMed]
158. Chikka MR, McCabe DD, Tyra HM, Rutkowski DT. 2013. C/EBP homologous protein (CHOP) contributes to suppression of metabolic genes during endoplasmic reticulum stress in the liver. J Biol Chem 288:4405–4415. [PubMed][CrossRef]
159. Thevenot PT, Sierra RA, Raber PL, Al-Khami AA, Trillo-Tinoco J, Zarreii P, Ochoa AC, Cui Y, Del Valle L, Rodriguez PC. 2014. The stress-response sensor chop regulates the function and accumulation of myeloid-derived suppressor cells in tumors. Immunity 41:389–401. [PubMed][CrossRef]
160. Bunt SK, Clements VK, Hanson EM, Sinha P, Ostrand-Rosenberg S. 2009. Inflammation enhances myeloid-derived suppressor cell cross-talk by signaling through Toll-like receptor 4. J Leukoc Biol 85:996–1004. [PubMed][CrossRef]
161. Greifenberg V, Ribechini E, Rössner S, Lutz MB. 2009. Myeloid-derived suppressor cell activation by combined LPS and IFN-γ treatment impairs DC development. Eur J Immunol 39:2865–2876. [PubMed][CrossRef]
162. Liu Y, Xiang X, Zhuang X, Zhang S, Liu C, Cheng Z, Michalek S, Grizzle W, Zhang HG. 2010. Contribution of MyD88 to the tumor exosome-mediated induction of myeloid derived suppressor cells. Am J Pathol 176:2490–2499. [PubMed][CrossRef]
163. Capietto AH, Kim S, Sanford DE, Linehan DC, Hikida M, Kumosaki T, Novack DV, Faccio R. 2013. Down-regulation of PLCγ2–β-catenin pathway promotes activation and expansion of myeloid-derived suppressor cells in cancer. J Exp Med 210:2257–2271. [PubMed][CrossRef]
164. Pilon-Thomas S, Nelson N, Vohra N, Jerald M, Pendleton L, Szekeres K, Ghansah T. 2011. Murine pancreatic adenocarcinoma dampens SHIP-1 expression and alters MDSC homeostasis and function. PLoS One 6:e27729. doi:10.1371/journal.pone.0027729. [PubMed][CrossRef]
165. Guo G, Marrero L, Rodriguez P, Del Valle L, Ochoa A, Cui Y. 2013. Trp53 inactivation in the tumor microenvironment promotes tumor progression by expanding the immunosuppressive lymphoid-like stromal network. Cancer Res 73:1668–1675. [PubMed][CrossRef]
166. Li L, Zhang J, Diao W, Wang D, Wei Y, Zhang CY, Zen K. 2014. MicroRNA-155 and MicroRNA-21 promote the expansion of functional myeloid-derived suppressor cells. J Immunol 192:1034–1043. [PubMed][CrossRef]
167. Sonda N, Simonato F, Peranzoni E, Calì B, Bortoluzzi S, Bisognin A, Wang E, Marincola FM, Naldini L, Gentner B, Trautwein C, Sackett SD, Zanovello P, Molon B, Bronte V. 2013. miR-142-3p prevents macrophage differentiation during cancer-induced myelopoiesis. Immunity 38:1236–1249. [PubMed][CrossRef]
168. Stromnes IM, Brockenbrough JS, Izeradjene K, Carlson MA, Cuevas C, Simmons RM, Greenberg PD, Hingorani SR. 2014. Targeted depletion of an MDSC subset unmasks pancreatic ductal adenocarcinoma to adaptive immunity. Gut 63:1769–1781. [PubMed][CrossRef]
169. Vincent J, Mignot G, Chalmin F, Ladoire S, Bruchard M, Chevriaux A, Martin F, Apetoh L, Rebe C, Ghiringhelli F. 2010. 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res 70:3052–3061. [PubMed][CrossRef]
170. Suzuki E, Kapoor V, Jassar AS, Kaiser LR, Albelda SM. 2005. Gemcitabine selectively eliminates splenic Gr-1 +/CD11b + myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin Cancer Res 11:6713–6721. [PubMed][CrossRef]
171. Kodumudi KN, Woan K, Gilvary DL, Sahakian E, Wei S, Djeu JY. 2010. A novel chemoimmunomodulating property of docetaxel: suppression of myeloid-derived suppressor cells in tumor bearers. Clin Cancer Res 16:4583–4594. [PubMed][CrossRef]
172. Alizadeh D, Trad M, Hanke NT, Larmonier CB, Janikashvili N, Bonnotte B, Katsanis E, Larmonier N. 2014. Doxorubicin eliminates myeloid-derived suppressor cells and enhances the efficacy of adoptive T-cell transfer in breast cancer. Cancer Res 74:104–118. [PubMed][CrossRef]
173. Bronte V, Chappell DB, Apolloni E, Cabrelle A, Wang M, Hwu P, Restifo NP. 1999. Unopposed production of granulocyte-macrophage colony-stimulating factor by tumors inhibits CD8 + T cell responses by dysregulating antigen-presenting cell maturation. J Immunol 162:5728–5737. [PubMed]
174. Qian BZ, Li J, Zhang H, Kitamura T, Zhang J, Campion LR, Kaiser EA, Snyder LA, Pollard JW. 2011. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475:222–225. [PubMed][CrossRef]
175. Ries CH, Cannarile MA, Hoves S, Benz J, Wartha K, Runza V, Rey-Giraud F, Pradel LP, Feuerhake F, Klaman I, Jones T, Jucknischke U, Scheiblich S, Kaluza K, Gorr IH, Walz A, Abiraj K, Cassier PA, Sica A, Gomez-Roca C, de Visser KE, Italiano A, Le Tourneau C, Delord JP, Levitsky H, Blay JY, Rüttinger D. 2014. Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell 25:846–859. [PubMed][CrossRef]
176. Shojaei F, Wu X, Qu X, Kowanetz M, Yu L, Tan M, Meng YG, Ferrara N. 2009. G-CSF-initiated myeloid cell mobilization and angiogenesis mediate tumor refractoriness to anti-VEGF therapy in mouse models. Proc Natl Acad Sci U S A 106:6742–6747. [PubMed][CrossRef]
177. Sumida K, Wakita D, Narita Y, Masuko K, Terada S, Watanabe K, Satoh T, Kitamura H, Nishimura T. 2012. Anti-IL-6 receptor mAb eliminates myeloid-derived suppressor cells and inhibits tumor growth by enhancing T-cell responses. Eur J Immunol 42:2060–2072. [PubMed][CrossRef]
178. Guiducci C, Vicari AP, Sangaletti S, Trinchieri G, Colombo MP. 2005. Redirecting in vivo elicited tumor infiltrating macrophages and dendritic cells towards tumor rejection. Cancer Res 65:3437–3446. [PubMed]
179. Weiss JM, Ridnour LA, Back T, Hussain SP, He P, Maciag AE, Keefer LK, Murphy WJ, Harris CC, Wink DA, Wiltrout RH. 2010. Macrophage-dependent nitric oxide expression regulates tumor cell detachment and metastasis after IL-2/anti-CD40 immunotherapy. J Exp Med 207:2455–2467. [PubMed][CrossRef]
180. Yang L, Huang J, Ren X, Gorska AE, Chytil A, Aakre M, Carbone DP, Matrisian LM, Richmond A, Lin PC, Moses HL. 2008. Abrogation of TGFβ signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. Cancer Cell 13:23–35. [PubMed][CrossRef]
181. Nagaraj S, Youn JI, Weber H, Iclozan C, Lu L, Cotter MJ, Meyer C, Becerra CR, Fishman M, Antonia S, Sporn MB, Liby KT, Rawal B, Lee JH, Gabrilovich DI. 2010. Anti-inflammatory triterpenoid blocks immune suppressive function of MDSCs and improves immune response in cancer. Clin Cancer Res 16:1812–1823. [PubMed][CrossRef]
182. Ko JS, Rayman P, Ireland J, Swaidani S, Li G, Bunting KD, Rini B, Finke JH, Cohen PA. 2010. Direct and differential suppression of myeloid-derived suppressor cell subsets by sunitinib is compartmentally constrained. Cancer Res 70:3526–3536. [PubMed][CrossRef]
183. Ozao-Choy J, Ma G, Kao J, Wang GX, Meseck M, Sung M, Schwartz M, Divino CM, Pan PY, Chen SH. 2009. The novel role of tyrosine kinase inhibitor in the reversal of immune suppression and modulation of tumor microenvironment for immune-based cancer therapies. Cancer Res 69:2514–2522. [PubMed][CrossRef]
184. van Cruijsen H, van der Veldt AA, Vroling L, Oosterhoff D, Broxterman HJ, Scheper RJ, Giaccone G, Haanen JB, van den Eertwegh AJ, Boven E, Hoekman K, de Gruijl TD. 2008. Sunitinib-induced myeloid lineage redistribution in renal cell cancer patients: CD1c + dendritic cell frequency predicts progression-free survival. Clin Cancer Res 14:5884–5892. [PubMed][CrossRef]
185. Sinha P, Clements VK, Fulton AM, Ostrand-Rosenberg S. 2007. Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells. Cancer Res 67:4507–4513. [PubMed][CrossRef]
186. Rodriguez PC, Hernandez CP, Quiceno D, Dubinett SM, Zabaleta J, Ochoa JB, Gilbert J, Ochoa AC. 2005. Arginase I in myeloid suppressor cells is induced by COX-2 in lung carcinoma. J Exp Med 202:931–939. [PubMed][CrossRef]
187. Veltman JD, Lambers ME, van Nimwegen M, Hendriks RW, Hoogsteden HC, Aerts JG, Hegmans JP. 2010. COX-2 inhibition improves immunotherapy and is associated with decreased numbers of myeloid-derived suppressor cells in mesothelioma. Celecoxib influences MDSC function. BMC Cancer 10:464. doi:10.1186/1471-2407-10-464. [CrossRef]
188. Serafini P, Meckel K, Kelso M, Noonan K, Califano J, Koch W, Dolcetti L, Bronte V, Borrello I. 2006. Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J Exp Med 203:2691–2702. [PubMed][CrossRef]
189. Noonan KA, Ghosh N, Rudraraju L, Bui M, Borrello I. 2014. Targeting immune suppression with PDE5 inhibition in end-stage multiple myeloma. Cancer Immunol Res 2:725–731. [PubMed][CrossRef]
190. Weed DT, Vella JL, Reis IM, De la Fuente AC, Gomez C, Sargi Z, Nazarian R, Califano J, Borrello I, Serafini P. 2015. Tadalafil reduces myeloid-derived suppressor cells and regulatory T cells and promotes tumor immunity in patients with head and neck squamous cell carcinoma. Clin Cancer Res 21:39–48. [PubMed][CrossRef]
191. De Santo C, Serafini P, Marigo I, Dolcetti L, Bolla M, Del Soldato P, Melani C, Guiducci C, Colombo MP, Iezzi M, Musiani P, Zanovello P, Bronte V. 2005. Nitroaspirin corrects immune dysfunction in tumor-bearing hosts and promotes tumor eradication by cancer vaccination. Proc Natl Acad Sci U S A 102:4185–4190. [PubMed][CrossRef]
192. Nefedova Y, Fishman M, Sherman S, Wang X, Beg AA, Gabrilovich DI. 2007. Mechanism of all- trans retinoic acid effect on tumor-associated myeloid-derived suppressor cells. Cancer Res 67:11021–11028. [PubMed][CrossRef]
193. Mirza N, Fishman M, Fricke I, Dunn M, Neuger AM, Frost TJ, Lush RM, Antonia S, Gabrilovich DI. 2006. All- trans-retinoic acid improves differentiation of myeloid cells and immune response in cancer patients. Cancer Res 66:9299–9307. [PubMed][CrossRef]
194. Garrity T, Pandit R, Wright MA, Benefield J, Keni S, Young MR. 1997. Increased presence of CD34 + cells in the peripheral blood of head and neck cancer patients and their differentiation into dendritic cells. Int J Cancer 73:663–669. [PubMed][CrossRef]
195. Walsh JE, Clark AM, Day TA, Gillespie MB, Young MR. 2010. Use of α,25-dihydroxyvitamin D 3 treatment to stimulate immune infiltration into head and neck squamous cell carcinoma. Hum Immunol 71:659–665. [PubMed][CrossRef]
196. Beatty GL, Chiorean EG, Fishman MP, Saboury B, Teitelbaum UR, Sun W, Huhn RD, Song W, Li D, Sharp LL, Torigian DA, O’Dwyer PJ, Vonderheide RH. 2011. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 331:1612–1616. [PubMed][CrossRef]
197. Rolny C, Mazzone M, Tugues S, Laoui D, Johansson I, Coulon C, Squadrito ML, Segura I, Li X, Knevels E, Costa S, Vinckier S, Dresselaer T, Åkerud P, De Mol M, Salomäki H, Phillipson M, Wyns S, Larsson E, Buysschaert I, Botling J, Himmelreich U, Van Ginderachter JA, De Palma M, Dewerchin M, Claesson-Welsh L, Carmeliet P. 2011. HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF. Cancer Cell 19:31–44. [PubMed][CrossRef]
198. Veltman JD, Lambers ME, van Nimwegen M, Hendriks RW, Hoogsteden HC, Hegmans JP, Aerts JG. 2010. Zoledronic acid impairs myeloid differentiation to tumour-associated macrophages in mesothelioma. Br J Cancer 103:629–641. [PubMed][CrossRef]
199. Brown HK, Holen I. 2009. Anti-tumour effects of bisphosphonates—what have we learned from in vivo models? Curr Cancer Drug Targets 9:807–823. [PubMed][CrossRef]
200. Qin H, Lerman B, Sakamaki I, Wei G, Cha SC, Rao SS, Qian J, Hailemichael Y, Nurieva R, Dwyer KC, Roth J, Yi Q, Overwijk WW, Kwak LW. 2014. Generation of a new therapeutic peptide that depletes myeloid-derived suppressor cells in tumor-bearing mice. Nat Med 20:676–681. [PubMed][CrossRef]
201. Kotsakis A, Harasymczuk M, Schilling B, Georgoulias V, Argiris A, Whiteside TL. 2012. Myeloid-derived suppressor cell measurements in fresh and cryopreserved blood samples. J Immunol Methods 381:14–22. [PubMed][CrossRef]
202. Ko JS, Zea AH, Rini BI, Ireland JL, Elson P, Cohen P, Golshayan A, Rayman PA, Wood L, Garcia J, Dreicer R, Bukowski R, Finke JH. 2009. Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clin Cancer Res 15:2148–2157. [PubMed][CrossRef]

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Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous, immune-suppressive leukocyte population that develops systemically and infiltrates tumors. MDSCs can restrain the immune response through different mechanisms including essential metabolite consumption, reactive oxygen and nitrogen species production, as well as display of inhibitory surface molecules that alter T-cell trafficking and viability. Moreover, MDSCs play a role in tumor progression, acting directly on tumor cells and promoting cancer stemness, angiogenesis, stroma deposition, epithelial-to-mesenchymal transition, and metastasis formation. Many biological and pharmaceutical drugs affect MDSC expansion and functions in preclinical tumor models and patients, often reversing host immune dysfunctions and allowing a more effective tumor immunotherapy.

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MDSCs suppress the immune response by four main mechanisms. (1) MDSCs deplete essential metabolites for T lymphocyte fitness, such as -cysteine, -tryptophan (by the activation of IDO1), and -arginine (by the activation of both ARG1 and NOS2), inducing the T-cell proliferation arrest. T-cell proliferation block is exacerbated by MDSC-released TGF-β. -Arginine depletion by ARG1 activity also induces the translational repression of the CD3 ζ chain, which prevents T cells from responding to various stimuli. NO production inhibits T cells by interfering with the signaling cascade downstream of the IL-2 receptor. (2) High arginase activity in combination with increased NO production by the MDSCs not only results in more pronounced T-cell apoptosis but also leads to an increased production of ROS and RNS, such as the free radical peroxynitrite (ONOO), by the MDSCs. This process requires collaboration with NOX2 enzyme, which contributes to large amounts of ROS, such as HO, which then affect T-cell fitness by downregulating CD3 ζ-chain expression and reducing cytokine secretion. RNS can act on α and β TCR chains, preventing TCR signaling and promoting dissociation of CD3 ζ chain from the complex. (3) MDSCs interfere with T-cell migration and viability. MDSCs express the metalloproteinase ADAM17, able to cut the integrin CD62L on the T-cell membrane. RNS also modify leukocyte trafficking, promoting homing of immune-suppressive subsets other than T cells by tyrosine nitration of selective chemokines (like CCL2) or their receptors. MDSCs expressing PD-L1 can induce T-cell apoptosis by engaging PD-1. Moreover, NO produced by MDSCs has a direct proapoptotic role mediated by the accumulation of p53 and signaling by Fas, TNF receptor family members, and caspase-independent pathways. Finally, the MDSC-derived TGF-β can promote NK-cell inhibition. (4) MDSCs drive the differentiation of specific subsets into regulatory cells: by TGF-β release, MDSCs promote the clonal expansion of antigen-specific natural (n) Treg cells and drive the conversion of naive CD4 T cells into induced (i) Treg cells. MDSCs skew macrophages toward an M2 phenotype by release of IL-10. For abbreviations and more details, see the text.

Source: microbiolspec May 2016 vol. 4 no. 3 doi:10.1128/microbiolspec.MCHD-0016-2015
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Surface and molecular markers of mouse and human MDSCs

Source: microbiolspec May 2016 vol. 4 no. 3 doi:10.1128/microbiolspec.MCHD-0016-2015
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A synopsis of drugs targeting MDSCs

Source: microbiolspec May 2016 vol. 4 no. 3 doi:10.1128/microbiolspec.MCHD-0016-2015

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