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Chapter 49 : Tumor-Induced Myeloid-Derived Suppressor Cells

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Abstract:

Tumors are composed of heterogeneous, transformed cell populations with different morphologies and phenotypes, which are organized in a pyramidal architecture determined by self-renewal ability, differentiation grade, and tumorigenic and clonogenic potential ( ). During tumor progression, cancer cells secrete tumor-derived factors (TDFs), like cytokines, chemokines, and metabolites, which promote the development of a flexible microenvironment inducing both the generation of new vessels and the modification of the immune responses ( ). Tumors can escape the immune system by three main mechanisms: (i) cancer cells can veil their identity to escape recognition by immune effectors, (ii) they can directly modify antitumor immunity, or (iii) they can recruit other immune regulatory cells whose normal function is to inhibit immune reactions and prevent the unfavorable effects of uncontrolled immune stimulation ( ). Probably the most pervasive and efficient strategy of “tumor escape” relies on the tumor’s ability to create a tolerant microenvironment by modification of normal hematopoiesis. In fact, cancers can induce the proliferation and differentiation of myeloid precursors into myeloid cells with immunosuppressive functions, in both the bone marrow and other hematopoietic organs such as the spleen, at the expense of additional myeloid cell subsets, such as dendritic cells (DCs) ( ). Additionally, the persisting imbalance in the number and type of myeloid cells can deeply influence myeloid cell recruitment and function at the tumor site and secondary lymphoid organs. In the bone marrow, hematopoietic progenitor cells give rise to immature DCs (iDCs). To reach complete maturation, iDCs require inflammation-related stimuli because, although able to take up, process, and present antigens, they express few or none of the costimulatory molecules, such as CD80, CD86, and CD40, necessary to exert their functions ( ). The higher number of iDCs found at the tumor site stems from defects in myelopoiesis rather than simply from the lack of appropriate activation signals at the tumor site. treatment of tumor-infiltrating DCs with appropriate stimuli—such as granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor α (TNF-α), or CD40L—was not sufficient to induce DC maturation; this evidence supports the concept that the reduced functionality of DCs is most likely due to defects in differentiation from their iDC progenitors ( ). However, iDCs are not the only myeloid cell populations modified in cancer. In postnatal life, hematopoietic stem cells present in hemopoietic compartments give rise to lymphoid and myeloid multipotent precursor cells. Other pluripotent cell types originate from the myeloid precursors: the common DCs and the immature myeloid cell precursors (IMCs). The first originates iDCs and plasmacytoid DCs, and the second is the common progenitor for macrophages, granulocytes, and monocyte-derived DCs ( ). In healthy mice, IMCs rapidly differentiate into their descendant lineages; consequently, they represent a relatively low percentage of circulating myeloid cells. However, under pathological conditions, including cancer, there is a partial block in IMC differentiation, leading to the accumulation of CD11b/Gr-1 myeloid cells with immunosuppressive function, named myeloid-derived suppressor cells (MDSCs) ( ).

Citation: De Sanctis F, Bronte V, Ugel S. 2017. Tumor-Induced Myeloid-Derived Suppressor Cells, p 833-856. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0016-2015
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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.

Citation: De Sanctis F, Bronte V, Ugel S. 2017. Tumor-Induced Myeloid-Derived Suppressor Cells, p 833-856. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0016-2015
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References

/content/book/10.1128/9781555819194.chap49
1. Frank NY,, Schatton T,, Frank MH . 2010. The therapeutic promise of the cancer stem cell concept. J Clin Invest 120 : 41 50.
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.
3. Schreiber RD,, Old LJ,, Smyth MJ . 2011. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331 : 1565 1570.
4. Drake CG,, Jaffee E,, Pardoll DM . 2006. Mechanisms of immune evasion by tumors. Adv Immunol 90 : 51 81.
5. Rabinovich GA,, Gabrilovich D,, Sotomayor EM . 2007. Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol 25 : 267 296.
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.
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.
8. Gabrilovich DI,, Nagaraj S . 2009. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9 : 162 174.
9. Strober S . 1984. Natural suppressor (NS) cells, neonatal tolerance, and total lymphoid irradiation: exploring obscure relationships. Annu Rev Immunol 2 : 219 237.
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.
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.
12. Kusmartsev S,, Gabrilovich DI . 2006. Role of immature myeloid cells in mechanisms of immune evasion in cancer. Cancer Immunol Immunother 55 : 237 245.
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.
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.
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.
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.
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.
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.
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.
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.
21. Talmadge JE,, Gabrilovich DI . 2013. History of myeloid-derived suppressor cells. Nat Rev Cancer 13 : 739 752.
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.
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.
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.
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.
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.
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.
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.
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.
30. Auffray C,, Sieweke MH,, Geissmann F . 2009. Blood monocytes: development, heterogeneity, and relationship with dendritic cells. Annu Rev Immunol 27 : 669 692.
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.
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.
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.
34. Gabrilovich DI,, Ostrand-Rosenberg S,, Bronte V . 2012. Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol 12 : 253 268.
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.
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.
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.
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.
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.
40. Biswas SK,, Mantovani A . 2010. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol 11 : 889 896.
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.
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.
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.
44. Wynn TA,, Chawla A,, Pollard JW . 2013. Macrophage biology in development, homeostasis and disease. Nature 496 : 445 455.
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.
46. Kobayashi Y . 2008. The role of chemokines in neutrophil biology. Front Biosci 13 : 2400 2407.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
74. Nagaraj S,, Gabrilovich DI . 2008. Tumor escape mechanism governed by myeloid-derived suppressor cells. Cancer Res 68 : 2561 2563.
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.
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.
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.
78. Rolinski J,, Hus I . 2014. Breaking immunotolerance of tumors: a new perspective for dendritic cell therapy. J Immunotoxicol 11 : 311 318.
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.
80. Bronte V,, Zanovello P . 2005. Regulation of immune responses by l-arginine metabolism. Nat Rev Immunol 5 : 641 654.
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.
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.
83. Baniyash M . 2004. TCR ζ-chain downregulation: curtailing an excessive inflammatory immune response. Nat Rev Immunol 4 : 675 687.
84. Rodriguez PC,, Quiceno DG,, Ochoa AC . 2007. l-Arginine availability regulates T-lymphocyte cell-cycle progression. Blood 109 : 1568 1573.
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.
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.
87. Bedard K,, Krause KH . 2007. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87 : 245 313.
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.
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.
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.
91. Alvarez B,, Radi R . 2003. Peroxynitrite reactivity with amino acids and proteins. Amino Acids 25 : 295 311.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
110. Ostrand-Rosenberg S,, Sinha P . 2009. Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol 182 : 4499 4506.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
143. Yoshimura A . 2006. Signal transduction of inflammatory cytokines and tumor development. Cancer Sci 97 : 439 447.
144. Kusmartsev S,, Gabrilovich DI . 2005. STAT1 signaling regulates tumor-associated macrophage-mediated T cell deletion. J Immunol 174 : 4880 4891.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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