Myeloid-derived suppressor cells in tumor-induced T cell suppression and tolerance

Tumor-Induced Immune Suppression: Mechanisms and Therapeutic Reversal

Volumn , Issue , 2014, Pages 99-150

  Serafini, Paolo ^a   Bronte, Vincenzo ^b  

^a UNIVERSITY OF MIAMI MILLER SCHOOL OF MEDICINE   (United States)

^b UNIVERSITY HOSPITAL OF VERONA   (Italy)

Author keywords

Clinical trials; Human myeloid derived suppressor cells; MDSC phenotype; Mechanisms of action; Mouse myeloid derived suppressor cells; Tumor derived factors; Tumor progression

Indexed keywords

EID: 84930023844     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1007/978-1-4899-8056-4_4     Document Type: Chapter

References (306)

1. Strober S (1984) Natural suppressor (NS) cells, neonatal tolerance, and total lymphoid irradiation: exploring obscure relationships. Annu Rev Immunol 2:219-237
2. Maier T, Holda JH, Claman HN (1989) Natural suppressor cells. Prog Clin Biol Res 288:235-244
3. Maier T, Holda JH, Claman HN (1985) Graft-vs-host reactions (GVHR) across minor murine histocompatibility barriers. II. Development of natural suppressor cell activity. J Immunol 135:1644-1651
4. Strober S, Dejbachsh-Jones S, Van Vlasselaer P, Duwe G, Salimi S, Allison JP (1989) Cloned natural suppressor cell lines express the CD3+CD4-CD8-surface phenotype and the alpha, beta heterodimer of the T cell antigen receptor. J Immunol 143:1118-1122
5. Sykes M, Sharabi Y, Sachs DH (1990) Natural suppressor cells in spleens of irradiated, bone marrow-reconstituted mice and normal bone marrow: lack of Sca-1 expression and enrichment by depletion of Mac1-positive cells. Cell Immunol 127:260-274
6. Subiza JL, Vinuela JE, Rodriguez R, Gil J, Figueredo MA, De La Concha EG (1989) Development of splenic natural suppressor (NS) cells in Ehrlich tumor-bearing mice. Int J Cancer 44:307-314
7. 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
8. Serafini P, Borrello I, Bronte V (2005) Myeloid suppressor cells in cancer: recruitment, phenotype, properties, and mechanisms of immune suppression. Semin Cancer Biol 16(1):53-65
9. Kusmartsev S, Gabrilovich DI (2006) Role of immature myeloid cells in mechanisms of immune evasion in cancer. Cancer Immunol Immunother 55(3):237-245. doi:10.1007/s00262-005-0048-z
10. 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(1): 425; author reply 426. doi:10.1158/0008-5472.CAN-06-3037
11. Fu YX, Watson G, Jimenez JJ, Wang Y, Lopez DM (1990) Expansion of immunoregulatory macrophages by granulocyte-macrophage colony-stimulating factor derived from a murine mammary tumor. Cancer Res 50:227-234
12. Melani C, Chiodoni C, Forni G, Colombo MP (2003) Myeloid cell expansion elicited by the progression of spontaneous mammary carcinomas in c-erbB-2 transgenic BALB/c mice suppresses immune reactivity. Blood 102(6):2138-2145
13. Bronte V, Apolloni E, Cabrelle A, Ronca R, Serafini P, Zamboni P, Restifo NP, Zanovello P (2000) Identification of a CD11b(+)/Gr-1(+)/CD31(+) myeloid progenitor capable of activating or suppressing CD8(+) T cells. Blood 96 (12):3838-3846
14. Kusmartsev S, Gabrilovich DI (2003) Inhibition of myeloid cell differentiation in cancer: the role of reactive oxygen species. J Leukoc Biol 74(2):186-196
15. Apolloni E, Bronte V, Mazzoni A, Serafini P, Cabrelle A, Segal DM, Young HA, Zanov-ello P (2000) Immortalized myeloid suppressor cells trigger apoptosis in antigen-activated T lymphocytes. J Immunol 165(12):6723-6730
16. 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(1):22-35. doi:10.1002/eji.200939903
17. 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(12):3533-3544
18. 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/EBPbeta transcription factor. Immunity 32(6):790-802. doi:10.1016/j.immuni.2010.05.010
19. 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(3):323-331
20. Salvadori S, Martinelli G, Zier K (2000) Resection of solid tumors reverses T cell defects and restores protective immunity. J Immunol 164(4):2214-2220
21. Danna EA, Sinha P, Gilbert M, Clements VK, Pulaski BA, Ostrand-Rosenberg S (2004) Surgical removal of primary tumor reverses tumor-induced immunosuppression despite the presence of metastatic disease. Cancer Res 64(6):2205-2211
22. Sinha P, Clements VK, Miller S, Ostrand-Rosenberg S (2005) Tumor immunity: a balancing act between T cell activation, macrophage activation and tumor-induced immune suppression. Cancer Immunol Immunother 54(11):1137-1142
23. Terabe M, Matsui S, Park JM, Mamura M, Noben-Trauth N, Donaldson DD, Chen W, Wahl SM, Ledbetter S, Pratt B, Letterio JJ, Paul WE, Berzofsky JA (2003) Transforming growth factor-beta production and myeloid cells are an effector mechanism through which CD1d-restricted T cells block cytotoxic T lymphocyte-mediated tumor immunosurveillance: abrogation prevents tumor recurrence. J Exp Med 198(11):1741-1752
24. Bronte V, Wang M, Overwijk WW, Surman DR, Pericle F, Rosenberg SA, Restifo NP (1998) Apoptotic death of CD8+ T lymphocytes after immunization: induction of a suppressive population of Mac-1+/Gr-1+ cells. J Immunol 161(10):5313-5320
25. 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(10):5728-5737
26. 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(7):931-939
27. 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(11):4185-4190. doi:10.1073/pnas.0409783102
28. 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(12):2691-2702. doi:10.1084/jem.20061104
29. Gallina G, Dolcetti L, Serafini P, Santo CD, 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(10): 2777-2790
30. Kusmartsev S, Gabrilovich DI (2005) STAT1 signaling regulates tumor-associated macroph-age-mediated T cell deletion. J Immunol 174(8):4880-4891
31. 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(15):4441-4449
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. 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(8):4233-4244. doi:10.1182/blood-2007-07-099226
34. 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(2):238-244. doi:10.1016/j.coi.2010.01.021
35. Auffray C, Sieweke MH, Geissmann F (2009) Blood monocytes: development, heterogeneity, and relationship with dendritic cells. Annu Rev Immunol 27:669-692. doi:10.1146/annurev.immunol.021908.132557
36. Gabrilovich DI, Nagaraj S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9(3):162-174. doi:10.1038/nri2506
37. Elkabets M, Ribeiro VS, Dinarello CA, Ostrand-Rosenberg S, Di Santo JP, Apte RN, Vosshenrich CA (2010) IL-1beta regulates a novel myeloid-derived suppressor cell subset that impairs NK cell development and function. Eur J Immunol 40(12):3347-3357. doi:10.1002/eji.201041037
38. Kusmartsev S, Su Z, Heiser A, Dannull J, Eruslanov E, Kubler H, Yancey D, Dahm P, Vieweg J (2008) Reversal of myeloid cell-mediated immunosuppression in patients with metastatic renal cell carcinoma. Clin Cancer Res 14(24):8270-8278. doi:10.1158/1078-0432.CCR-08-0165
39. 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(4):1553-1560. doi:10.1158/0008-5472.CAN-08-1921
40. Schmielau J, Finn OJ (2001) Activated granulocytes and granulocyte-derived hydrogen peroxide are the underlying mechanism of suppression of T cell function in advanced cancer patients. Cancer Res 61(12):4756-4760
41. 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(9):5693-5701. doi:10.4049/jimmunol.0900092
42. 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. doi:10.1038/ni.2526
43. Beckman JS, Koppenol WH (1996) Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am J Physiol 271(5 Pt 1):C1424-C1437
44. 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(6):1373-1383. doi:10.1158/0008-5472.CAN-11-2772
45. 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 Reports 2(3):628-639. doi:10.1016/j.celrep.2012.08.006
46. Serafini P, De Santo C, Marigo I, Cingarlini S, Dolcetti L, Gallina G, Zanovello P, Bronte V (2004) Derangement of immune responses by myeloid suppressor cells. Cancer Immunol Immunother 53(2):64-72. doi:10.1007/s00262-003-0443-2
47. Horiguchi S, Petersson M, Nakazawa T, Kanda M, Zea AH, Ochoa AC, Kiessling R (1999) Primary chemically induced tumors induce profound immunosuppression concomitant with apoptosis and alterations in signal transduction in T cells and NK cells. Cancer Res 59(12):2950-2956
48. Talmadge JE, Hood KC, Zobel LC, Shafer LR, Coles M, Toth B (2007) Chemoprevention by cyclooxygenase-2 inhibition reduces immature myeloid suppressor cell expansion. Int Immunopharmacol 7(2):140-151
49. Liu Y, Van Ginderachter JA, Brys L, De Baetselier P, Raes G, Geldhof AB (2003) Nitric oxide-independent CTL suppression during tumor progression: association with arginase-producing (M2) myeloid cells. J Immunol 170(10):5064-5074
50. Park JM, Terabe M, van den Broeke LT, Donaldson DD, Berzofsky JA (2005) Unmasking im-munosurveillance against a syngeneic colon cancer by elimination of CD4+ NKT regulatory cells and IL-13. Int J Cancer 114(1):80-87
51. 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(4):409-421
52. Young MR, Cigal M (2006) Tumor skewing of CD34+ cell differentiation from a dendritic cell pathway into endothelial cells. Cancer Immunol Immunother 55(5):558-568
53. De Palma M, Venneri MA, Galli R, Sergi Sergi L, Politi LS, Sampaolesi M, Naldini L (2005) Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell 8(3):211-226
54. Gabrilovich DI, Chen HL, Girgis KR, Cunningham HT, Meny GM, Nadaf S, Kavanaugh D, Carbone DP (1996) Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med 2:1096-1103
55. Young MR, Young ME, Wright MA (1990) Myelopoiesis-associated suppressor-cell activity in mice with Lewis lung carcinoma tumors: interferon-gamma plus tumor necrosis factor-alpha synergistically reduce suppressor cell activity. Int J Cancer 46(2):245-250
56. Pegoraro L, Fierro MT, Lusso P, Giovinazzo B, Lanino E, Giovarelli M, Matera L, Foa R (1985) A novel leukemia T cell line (PF-382) with phenotypic and functional features of suppressor lymphocytes. J Natl Cancer Inst 75(2):285-290
57. Cirillo C, Montaldo P, Lanciotti M, Parodi MT, Castagnola E, Ponzoni M (1988) Immuno-suppressive factors produced by a T cell line derived from acute lymphoblastic leukemia. Boll Ist Sieroter Milan 67(4):295-308
58. Lim SH, Worman CP, Jewell A, Goldstone AH (1991) Production of tumour-derived suppressor factor in patients with acute myeloid leukaemia. Leuk Res 15(4):263-268
59. Kunicka JE, Fox FE, Seki H, Oleszak EL, Platsoucas CD (1991) Hybridoma-derived human suppressor factors: inhibition of growth of tumor cell lines and effect on cytotoxic cells. Hum Antibodies Hybridomas 2(3):160-169
60. Young MR, Wright MA, Coogan M, Young ME, Bagash J (1992) Tumor-derived cytokines induce bone marrow suppressor cells that mediate immunosuppression through transforming growth factor beta. Cancer Immunol Immunother 35(1):14-18
61. Moore SC, Shaw MA, Soderberg LS (1992) Transforming growth factor-beta is the major mediator of natural suppressor cells derived from normal bone marrow. J Leukoc Biol 52(6):596-601
62. Heldin CH (2004) Development and possible clinical use of antagonists for PDGF and TGF-beta. Ups J Med Sci 109(3):165-178
63. Serafini P, Borrello I, Bronte V (2006) Myeloid suppressor cells in cancer: recruitment, phe-notype, properties, and mechanisms of immune suppression. Semin Cancer Biol 16(1):53-65. doi:10.1016/j.semcancer.2005.07.005
64. Hamilton JA (2008) Colony-stimulating factors in inflammation and autoimmunity. Nat Rev Immunol 8(7):533-544. doi:10.1038/nri2356
65. Lin EY, Nguyen AV, Russell RG, Pollard JW (2001) Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J Exp Med 193(6):727-740
66. Paulus P, Stanley ER, Schafer R, Abraham D, Aharinejad S (2006) Colony-stimulating factor-1 antibody reverses chemoresistance in human MCF-7 breast cancer xenografts. Cancer Res 66(8):4349-4356. doi:10.1158/0008-5472.CAN-05-3523
67. Eubank TD, Galloway M, Montague CM, Waldman WJ, Marsh CB (2003) M-CSF induces vascular endothelial growth factor production and angiogenic activity from human monocytes. J Immunol 171(5):2637-2643
68. Rambaldi A, Wakamiya N, Vellenga E, Horiguchi J, Warren MK, Kufe D, Griffin JD (1988) Expression of the macrophage colony-stimulating factor and c-fms genes in human acute myeloblastic leukemia cells. J Clin Invest 81(4):1030-1035
69. Haran-Ghera N, Krautghamer R, Lapidot T, Peled A, Dominguez MG, Stanley ER (1997) Increased circulating colony-stimulating factor-1 (CSF-1) in SJL/J mice with radiation-induced acute myeloid leukemia (AML) is associated with autocrine regulation of AML cells by CSF-1. Blood 89(7):2537-2545
70. 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(5):821-827
71. Champelovier P, Boucard N, Levacher G, Simon A, Seigneurin D, Praloran V (2002) Plasminogen-and colony-stimulating factor-1-associated markersinbladder carcinoma: diagnostic value of urokinase plasminogen activator receptor and plasminogen activator inhibitor type-2 using immunocytochemical analysis. Urol Res 30(5):301-309
72. 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(2):147-162
73. Menetrier-Caux C, Montmain G, Dieu MC, Bain C, Favrot MC, Caux C, Blay JY (1998) Inhibition of the differentiation of dendritic cells from CD34(+) progenitors by tumor cells: role of interleukin-6 and macrophage colony-stimulating factor. Blood 92(12):4778-4791
74. Korsgren M, Persson CG, Sundler F, Bjerke T, Hansson T, Chambers BJ, Hong S, Van Kaer L, Ljunggren HG, Korsgren O (1999) Natural killer cells determine development of allergen-induced eosinophilic airway inflammation in mice. J Exp Med 189(3):553-562
75. Huang B, Pan PY, Li Q, Sato AI, Levy DE, Bromberg J, Divino CM, Chen SH (2006) Gr-1+CD115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T cell anergy in tumor-bearing host. Cancer Res 66(2):1123-1131. doi:10.1158/0008-5472.CAN-05-1299
76. 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(7):1461-1471. doi:10.1182/blood-2009-08-237412
77. 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(13):4653-4665
78. Akira S, Taga T, Kishimoto T (1993) Interleukin-6 in biology and medicine. Adv Immunol 54:1-78
79. Hirano T (1992) The biology of interleukin-6. Chem Immunol 51:153-180
80. Kishimoto T (1989) The biology of interleukin-6. Blood 74(1):1-10
81. Naugler WE, Karin M (2008) The wolf in sheep's clothing: the role of interleukin-6 in immunity, inflammation and cancer. Trends Mol Med 14(3):109-119. doi:10.1016/j.molmed.2007.12.007
82. Tamura T, Udagawa N, Takahashi N, Miyaura C, Tanaka S, Yamada Y, Koishihara Y, Ohsugi Y, Kumaki K, Taga T, et al. (1993) Soluble interleukin-6 receptor triggers osteoclast formation by interleukin 6. Proc Natl Acad Sci U S A 90(24):11924-11928
83. Rose-John S (2012) IL-6 trans-signaling via the soluble IL-6 receptor: importance for the pro-inflammatory activities of IL-6. Int J Biol Sci 8(9):1237-1247. doi:10.7150/ijbs.4989
84. Park SJ, Nakagawa T, Kitamura H, Atsumi T, Kamon H, Sawa S, Kamimura D, Ueda N, Iwakura Y, Ishihara K, Murakami M, Hirano T (2004) IL-6 regulates in vivo dendritic cell differentiation through STAT3 activation. J Immunol 173(6):3844-3854
85. Ratta M, Fagnoni F, Curti A, Vescovini R, Sansoni P, Oliviero B, Fogli M, Ferri E, Della Cuna GR, Tura S, Baccarani M, Lemoli RM (2002) Dendritic cells are functionally defective in multiple myeloma: the role of interleukin-6. Blood 100(1):230-237
86. Hayashi T, Hideshima T, Akiyama M, Raje N, Richardson P, Chauhan D, Anderson KC (2003) Ex vivo induction of multiple myeloma-specific cytotoxic T lymphocytes. Blood 102(4):1435-1442
87. Wang S, Yang J, Qian J, Wezeman M, Kwak LW, Yi Q (2006) Tumor evasion of the immune system: inhibiting p38 MAPK signaling restores the function of dendritic cells in multiple myeloma. Blood 107(6):2432-2439
88. 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(8):2060-2072. doi:10.1002/eji.201142335
89. Wu CT, Hsieh CC, Lin CC, Chen WC, Hong JH, Chen MF (2012) Significance of IL-6 in the transition of hormone-resistant prostate cancer and the induction of myeloid-derived suppressor cells. J Mol Med (Berl) 90(11):1343-1355. doi:10.1007/s00109-012-0916-x
90. Sevko A, Umansky V (2013) Myeloid-derived suppressor cells interact with tumors in terms of myelopoiesis, tumorigenesis and immunosuppression: thick as thieves. J Cancer 4(1):3-11. doi:10.7150/jca.5047
91. Lechner MG, Megiel C, Russell SM, Bingham B, Arger N, Woo T, Epstein AL (2011) Functional characterization of human Cd33+ and Cd11b+ myeloid-derived suppressor cell subsets induced from peripheral blood mononuclear cells co-cultured with a diverse set of human tumor cell lines. J Transl Med 9:90. doi:10.1186/1479-5876-9-90
92. Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307 (5706) :58-62
93. Toi M, Kondo S, Suzuki H, Yamamoto Y, Inada K, Imazawa T, Taniguchi T, Tominaga T (1996) Quantitative analysis of vascular endothelial growth factor in primary breast cancer. Cancer 77(6):1101-1106
94. Gabrilovich D, Ishida T, Oyama T, Ran S, Kravtsov V, Nadaf S, Carbone DP (1998) Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood 92(11):4150-4166
95. Gabrilovich D (2004) Mechanisms and functional significance of tumour-induced dendritic-cell defects. Nat Rev Immunol 4(12):941-952
96. Parenti A, Morbidelli L, Cui XL, Douglas JG, Hood JD, Granger HJ, Ledda F, Ziche M (1998) Nitric oxide is an upstream signal of vascular endothelial growth factor-induced extracellular signal-regulated kinase1/2 activation in postcapillary endothelium. J Biol Chem 273(7): 4220-4226
97. Kimura H, Weisz A, Ogura T, Hitomi Y, Kurashima Y, Hashimoto K, D'Acquisto F, Makuuchi M, Esumi H (2001) Identification of hypoxia-inducible factor 1 ancillary sequence and its function in vascular endothelial growth factor gene induction by hypoxia and nitric oxide. J Biol Chem 276(3):2292-2298. doi:10.1074/jbc.M008398200
98. Jayaraman P, Parikh F, Lopez-Rivera E, Hailemichael Y, Clark A, Ma G, Cannan D, Ramacher M, Kato M, Overwijk WW, Chen SH, Umansky VY, Sikora AG (2012) Tumor-expressed inducible nitric oxide synthase controls induction of functional myeloid-derived suppressor cells through modulation of vascular endothelial growth factor release. J Immunol 188(11):5365-5376. doi:10.4049/jimmunol.1103553
99. 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(10):1949-1962. doi:10.1084/jem.20101956
100. Smith CW, Chen Z, Dong G, Loukinova E, Pegram MY, Nicholas-Figueroa L, Van Waes C (1998) The host environment promotes the development of primary and metastatic squamous cell carcinomas that constitutively express proinflammatory cytokines IL-1alpha, IL-6, GM-CSF, and KC. Clin Exp Metastasis 16(7):655-664
101. Merchav S, Apte RN, Tatarsky I, Ber R (1987) Effect of plasmacytoma cells on the production of granulocyte-macrophage colony-stimulating activity (GM-CSA) in the spleen of tumor-bearing mice. Exp Hematol 15(9):995-1000
102. Takeda K, Hatakeyama K, Tsuchiya Y, Rikiishi H, Kumagai K (1991) A correlation between GM-CSF gene expression and metastases in murine tumors. Int J Cancer 47(3):413-420
103. Young MR, Wright MA, Young ME (1991) Antibodies to colony-stimulating factors block Lewis lung carcinoma cell stimulation of immune-suppressive bone marrow cells. Cancer Immunol Immunother 33:146-152
104. Young MR, Young ME, Wright MA (1990) Stimulation of immune-suppressive bone marrow cells by colony-stimulating factors. Exp Hematol 18(7):806-811.
105. Dranoff G (2002) GM-CSF-based cancer vaccines. Immunol Rev 188:147-154
106. Dranoff G (2003) GM-CSF-secreting melanoma vaccines. Oncogene 22(20):3188-3192
107. 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(17):6337-6343. doi:10.1158/0008-5472.CAN-04-0757
108. 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(2):226-232
109. 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(19):9518-9527
110. Pylayeva-Gupta Y, Lee KE, Hajdu CH, Miller G, Bar-Sagi D (2012) Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia. Cancer Cell 21(6):836-847
111. 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(6):822-835
112. Lesina M, Kurkowski MU, Ludes K, Rose-John S, Treiber M, Kloppel G, Yoshimura A, Reindl W, Sipos B, Akira S, Schmid RM, Algul H (2011) Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell 19(4):456-469
113. Fukuda A, Wang SC, Morris JP 4th, Folias AE, Liou A, Kim GE, Akira S, Boucher KM, Firpo MA, Mulvihill SJ, Hebrok M (2011) Stat3 and MMP7 contribute to pancreatic ductal adenocarcinoma initiation and progression. Cancer Cell 19(4):441-455
114. Schmidt K, Zilio S, Schmollinger JC, Bronte V, Blankenstein T, Willimsky G (2013) Differently immunogenic cancers in mice induce immature myeloid cells that suppress CTL in vitro but not in vivo following transfer. Blood 121(10):1740-1748. doi:10.1182/blood-2012-06-436568
115. Pawelec G (2004) Tumour escape: antitumour effectors too much of a good thing? Cancer Immunol Immunother 53(3):262-274
116. DeVita F, Orditura M, Galizia G, Romano C, Lieto E, Iodice P, Tuccillo C, Catalano G (2000) Serum interleukin-10 is an independent prognostic factor in advanced solid tumors. Oncol Rep 7(2):357-361
117. De Vita F, Orditura M, Galizia G, Romano C, Roscigno A, Lieto E, Catalano G (2000) Serum interleukin-10 levels as a prognostic factor in advanced non-small cell lung cancer patients. Chest 117(2):365-373
118. Chen ML, Wang FH, Lee PK, Lin CM (2001) Interleukin-10-induced T cell unresponsiveness can be reversed by dendritic cell stimulation. Immunol Lett 75(2):91-96
119. Steinbrink K, Graulich E, Kubsch S, Knop J, Enk AH (2002) CD4(+) and CD8(+) aner-gic T cells induced by interleukin-10-treated human dendritic cells display antigen-specific suppressor activity. Blood 99(7):2468-2476
120. Lan YY, Wang Z, Raimondi G, Wu W, Colvin BL, de Creus A, Thomson AW (2006) "Alternatively activated" dendritic cells preferentially secrete IL-10, expand Foxp3+CD4+ T cells, and induce long-term organ allograft survival in combination with CTLA4-Ig. J Immunol 177(9):5868-5877
121. 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(2):977-983
122. Hart KM, Byrne KT, Molloy MJ, Usherwood EM, Berwin B (2011) IL-10 immunomodulation of myeloid cells regulates a murine model of ovarian cancer. Front Immunol 2:29. doi:10.3389/fimmu.2011.00029
123. Bak SP, Walters JJ, Takeya M, Conejo-Garcia JR, Berwin BL (2007) Scavenger receptor-A-targeted leukocyte depletion inhibits peritoneal ovarian tumor progression. Cancer Res 67(10):4783-4789. doi:10.1158/0008-5472.CAN-06-4410
124. Peter S, Bak G, Hart K, Berwin B (2009) Ovarian tumor-induced T cell suppression is alleviated by vascular leukocyte depletion. Translat Oncol 2(4):291-299
125. Bak SP, Alonso A, Turk MJ, Berwin B (2008) Murine ovarian cancer vascular leukocytes require arginase-1 activity for T cell suppression. Mol Immunol 46(2):258-268. doi:10.1016/j.molimm.2008.08.266
126. Bronte V, Zanovello P (2005) Regulation of immune responses by L-arginine metabolism. Nat Rev Immunol 5(8):641-654. doi:10.1038/nri1668
127. Tanikawa T, Wilke CM, Kryczek I, Chen GY, Kao J, Nunez G, Zou W (2012) Interleukin-10 ablation promotes tumor development, growth, and metastasis. Cancer Res 72(2):420-429. doi:10.1158/0008-5472.CAN-10-4627
128. Terabe M, Park JM, Berzofsky JA (2004) Role of IL-13 in regulation of anti-tumor immunity and tumor growth. Cancer Immunol Immunother 53(2):79-85
129. Keegan AD, Nelms K, White M, Wang LM, Pierce JH, Paul WE (1994) AnIL-4receptorregion containing an insulin receptor motif is important for IL-4-mediated IRS-1 phosphorylation and cell growth. Cell 76(5):811-820
130. Gray MJ, Poljakovic M, Kepka-Lenhart D, Morris SM Jr. (2005) Induction of arginase I transcription by IL-4 requires a composite DNA response element for STAT6 and C/EBPbeta. Gene 353(1):98-106. doi:10.1016/j.gene.2005.04.004
131. 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(6):515-520.
132. Dunn GP, Old LJ, Schreiber RD (2004) The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21(2):137-148
133. Bach EA, Aguet M, Schreiber RD (1997) The IFN gamma receptor: a paradigm for cytokine receptor signaling. Annu Rev Immunol 15:563-591
134. Seliger B, Hohne A, Knuth A, Bernhard H, Meyer T, Tampe R, Momburg F, Huber C (1996) Analysis of the major histocompatibility complex class I antigen presentation machinery in normal and malignant renal cells: evidence for deficiencies associated with transformation and progression. Cancer Res 56(8):1756-1760
135. Ruegg C, Yilmaz A, Bieler G, Bamat J, Chaubert P, Lejeune FJ (1998) Evidence for the involvement of endothelial cell integrin alphaVbeta3 in the disruption of the tumor vasculature induced by TNF and IFN-gamma. Nat Med 4(4):408-414
136. Sgadari C, Angiolillo AL, Tosato G (1996) Inhibition of angiogenesis by interleukin-12 is mediated by the interferon-inducible protein 10. Blood 87(9):3877-3882
137. Dias S, Boyd R, Balkwill F (1998) IL-12 regulates VEGF and MMPs in a murine breast cancer model. Int J Cancer 78(3):361-365
138. Beatty GL, Paterson Y (2000) IFN-gamma can promote tumor evasion of the immune system in vivo by down-regulating cellular levels of an endogenous tumor antigen. J Immunol 165(10):5502-5508
139. Morel S, Levy F, Burlet-Schiltz O, Brasseur F, Probst-Kepper M, Peitrequin AL, Monsarrat B, Van Velthoven R, Cerottini JC, Boon T, Gairin JE, Van den Eynde BJ (2000) Processing of some antigens by the standard proteasome but not by the immunoproteasome results in poor presentation by dendritic cells. Immunity 12(1):107-117
140. Biswas SK, Gangi L, Paul S, Schioppa T, Saccani A, Sironi M, Bottazzi B, Doni A, Vincenzo B, Pasqualini F, Vago L, Nebuloni M, Mantovani A, Sica A (2006) A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-kappaB and enhanced IRF-3/STAT1 activation). Blood 107(5):2112-2122
141. MacMicking J, Xie QW, Nathan C (1997) Nitric oxide and macrophage function. Annu Rev Immunol 15:323-350
142. 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(2):689-695
143. Kaplan MH, Grusby MJ (1998) Regulation ofT helper cell differentiation bySTAT molecules. J Leukoc Biol 64(1):2-5
144. Sinha P, Clements VK, Ostrand-Rosenberg S (2005) Reduction of myeloid-derived suppressor cells and induction of M1 macrophages facilitate the rejection of established metastatic disease. J Immunol 174(2):636-645
145. Gasparini G, Longo R, Sarmiento R, Morabito A (2003) Inhibitors of cyclo-oxygenase 2: a new class of anticancer agents? Lancet Oncol 4(10):605-615
146. Sombroek CC, Stam AG, Masterson AJ, Lougheed SM, Schakel MJ, Meijer CJ, Pinedo HM, van den Eertwegh AJ, Scheper RJ, de Gruijl TD (2002) Prostanoids play a major role in the primary tumor-induced inhibition of dendritic cell differentiation. J Immunol 168(9): 4333-4343
147. Yang L, Yamagata N, Yadav R, Brandon S, Courtney RL, Morrow JD, Shyr Y, Boothby M, Joyce S, Carbone DP, Breyer RM (2003) Cancer-associated immunodeficiency and dendritic cell abnormalities mediated by the prostaglandin EP2 receptor. J Clin Invest 111(5):727-735
148. Serafini P (2010) Editorial: PGE2-producing MDSC: a role in tumor progression? J Leukoc Biol 88(5):827-829. doi:10.1189/jlb.0510303
149. Yoshimura A (2006) Signal transduction of inflammatory cytokines and tumor development. Cancer Sci 97(6):439-447
150. Rane SG, Reddy EP (2000) Janus kinases: components of multiple signaling pathways. Oncogene 19(49):5662-5679
151. Bromberg J (2002) Stat proteins and oncogenesis. J Clin Invest 109(9):1139-1142
152. Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE, Old LJ, Schreiber RD (2001) IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410 (6832) :1107-1111
153. Das J, Chen CH, Yang L, Cohn L, Ray P, Ray A (2001) A critical role for NF-kappa B in GATA3 expression and TH2 differentiation in allergic airway inflammation. Nat Immunol 2(1):45-50
154. Hanada T, Kobayashi T, Chinen T, Saeki K, Takaki H, Koga K, Minoda Y, Sanada T, Yoshioka T, Mimata H, Kato S, Yoshimura A (2006) IFNgamma-dependent, spontaneous development of colorectal carcinomas in SOCS1-deficient mice. J Exp Med 203(6):1391-1397
155. Alvaro T, Lejeune M, Camacho FI, Salvado MT, Sanchez L, Garcia JF, Lopez C, Jaen J, Bosch R, Pons LE, Bellas C, Piris MA (2006) The presence of STAT1-positive tumor-associated macrophages and their relation to outcome in patients with follicular lymphoma. Haematologica 91(12):1605-1612
156. Mora LB, Buettner R, Seigne J, Diaz J, Ahmad N, Garcia R, Bowman T, Falcone R, Fairclough R, Cantor A, Muro-Cacho C, Livingston S, Karras J, Pow-Sang J, Jove R (2002) Constitutive activation of Stat3 in human prostate tumors and cell lines: direct inhibition of Stat3 signaling induces apoptosis of prostate cancer cells. Cancer Res 62(22):6659-6666
157. Dolled-Filhart M, Camp RL, Kowalski DP, Smith BL, Rimm DL (2003) Tissue microarray analysis of signal transducers and activators of transcription 3 (Stat3) and phospho-Stat3 (Tyr705) in node-negative breast cancer shows nuclear localization is associated with a better prognosis. Clin Cancer Res 9(2):594-600
158. Nagpal JK, Mishra R, Das BR (2002) Activation of Stat-3 as one of the early events in tobacco chewing-mediated oral carcinogenesis. Cancer 94(9):2393-2400
159. Hsiao JR, Jin YT, Tsai ST, Shiau AL, Wu CL, Su WC (2003) Constitutive activation of STAT3 and STAT5 is present in the majority of nasopharyngeal carcinoma and correlates with better prognosis. Br J Cancer 89(2):344-349
160. Buettner R, Mora LB, Jove R (2002) Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin Cancer Res 8(4):945-954
161. Wang T, Niu G, Kortylewski M, Burdelya L, Shain K, Zhang S, Bhattacharya R, Gabrilovich D, Heller R, Coppola D, Dalton W, Jove R, Pardoll D, Yu H (2004) Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med 10(1):48-54
162. Cheng F, Wang HW, Cuenca A, Huang M, Ghansah T, Brayer J, Kerr WG, Takeda K, Akira S, Schoenberger SP, Yu H, Jove R, Sotomayor EM (2003) A critical role for Stat3 signaling in immune tolerance. Immunity 19(3):425-436
163. Kortylewski M, Kujawski M, Wang T, Wei S, Zhang S, Pilon-Thomas S, Niu G, Kay H, Mule J, Kerr WG, Jove R, Pardoll D, Yu H (2005) Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat Med 11(12):1314-1321
164. Nefedova Y, Huang M, Kusmartsev S, Bhattacharya R, Cheng P, Salup R, Jove R, Gabrilovich D (2004) Hyperactivation of STAT3 is involved in abnormal differentiation of dendritic cells in cancer. J Immunol 172(1):464-474
165. Nefedova Y, Cheng P, Gilkes D, Blaskovich M, Beg AA, Sebti SM, Gabrilovich DI (2005) Activation of dendritic cells via inhibition of Jak2/STAT3 signaling. J Immunol 175(7): 4338-4346
166. Kortylewski M, Swiderski P, Herrmann A, Wang L, Kowolik C, Kujawski M, Lee H, Scuto A, Liu Y, Yang C, Deng J, Soifer HS, Raubitschek A, Forman S, Rossi JJ, Pardoll DM, Jove R, Yu H (2009) In vivo delivery of siRNA to immune cells by conjugation to aTLR9 agonist enhances antitumor immune responses. Nat Biotechnol 27(10):925-932. doi:10.1038/nbt.1564
167. Yu H, Pardoll D, Jove R (2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9(11):798-809. doi:10.1038/nrc2734
168. Condamine T, Gabrilovich DI (2011) Molecular mechanisms regulating myeloid-derived suppressor cell differentiation and function. Trends Immunol 32(1):19-25. doi:10.1016/j.it.2010.10.002
169. Zhang H, Nguyen-Jackson H, Panopoulos AD, Li HS, Murray PJ, Watowich SS (2010) STAT3 controls myeloid progenitor growth during emergency granulopoiesis. Blood 116(14):2462-2471. doi:10.1182/blood-2009-12-259630
170. Sinha P, Okoro C, Foell D, Freeze HH, Ostrand-Rosenberg S, Srikrishna G (2008) Proin-flammatory S100 proteins regulate the accumulation of myeloid-derived suppressor cells. J Immunol 181(7):4666-4675
171. 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(10):2235-2249. doi:10.1084/jem.20080132
172. Takeda K, Clausen BE, Kaisho T, Tsujimura T, Terada N, Forster I, Akira S (1999) Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. Immunity 10(1):39-49
173. Lang R, Patel D, Morris JJ, Rutschman RL, Murray PJ (2002) Shaping gene expression in activated and resting primary macrophages by IL-10. J Immunol 169(5):2253-2263
174. Finder JD, Petrus JL, Hamilton A, Villavicencio RT, Pitt BR, Sebti SM (2001) Signal trans-duction pathways of IL-1beta-mediated iNOS in pulmonary vascular smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 281(4):L816-L823
175. Yu X, Kennedy RH, Liu SJ (2003) JAK2/STAT3, not ERK1/2, mediates interleukin-6-induced activation of inducible nitric-oxide synthase and decrease in contractility of adult ventricular myocytes. J Biol Chem 278(18):16304-16309
176. Yu Z, Zhang W, Kone BC (2002) Signal transducers and activators of transcription 3 (STAT3) inhibits transcription of the inducible nitric oxide synthase gene by interacting with nuclear factor kappaB. Biochem J 367(Pt 1):97-105
177. Ribechini E, Leenen PJ, Lutz MB (2009) Gr-1 antibody induces STAT signaling, macrophage marker expression and abrogation of myeloid-derived suppressor cell activity in BM cells. Eur J Immunol 39(12):3538-3551. doi:10.1002/eji.200939530
178. Quelle FW, Sato N, Witthuhn BA, Inhorn RC, Eder M, Miyajima A, Griffin JD, Ihle JN (1994) JAK2 associates with the beta c chain of the receptor for granulocyte-macrophage colony-stimulating factor, and its activation requires the membrane-proximal region. Mol Cell Biol 14(7):4335-4341
179. 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(3):511-519
180. Xin H, Zhang C, Herrmann A, Du Y, Figlin R, Yu H (2009) Sunitinib inhibitionofStat3 induces renal cell carcinoma tumor cell apoptosis and reduces immunosuppressive cells. Cancer Res 69(6):2506-2513. doi:10.1158/0008-5472.CAN-08-4323
181. 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 immuno-logic escape. Immunol Invest 41(6-7):680-710. doi:10.3109/08820139.2012.703745
182. 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-gamma dependent. J Immunol 169(10):5796-5804
183. 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(1):120-126. doi:10.1097/SLA. 0b013e3181bfda1c
184. Lesterhuis WJ, Punt CJ, Hato SV, Eleveld-Trancikova D, Jansen BJ, Nierkens S, Schreibelt G, de Boer A, Van Herpen CM, Kaanders JH, van Krieken JH, Adema GJ, Figdor CG, de Vries IJ (2011) Platinum-based drugs disrupt STAT6-mediated suppression of immune responses against cancer in humans and mice. J Clin Invest 121(8):3100-3108. doi:10.1172/JCI43656
185. Arranz A, Doxaki C, Vergadi E, Martinez de la Torre Y, Vaporidi K, Lagoudaki ED, Ieronymaki E, Androulidaki A, Venihaki M, Margioris AN, Stathopoulos EN, Tsichlis PN, Tsatsanis C (2012) Akt1 and Akt2 protein kinases differentially contribute to macrophage polarization. Proc Natl Acad Sci U S A 109(24):9517-9522. doi:10.1073/pnas.1119038109
186. Ruffell D, Mourkioti F, Gambardella A, Kirstetter P, Lopez RG, Rosenthal N, Nerlov C (2009) A CREB-C/EBPbeta cascade induces M2 macrophage-specific gene expression and promotes muscle injury repair. Proc Natl Acad Sci U S A 106(41):17475-17480. doi:10.1073/pnas.0908641106
187. Lawrence T, Natoli G (2011) Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nat Rev Immunol 11(11):750-761. doi:10.1038/nri3088
188. Laiosa CV, Stadtfeld M, Xie H, de Andres-Aguayo L, Graf T (2006) Reprogramming of committed T cell progenitors to macrophages and dendritic cells by C/EBP alpha and PU.1 transcription factors. Immunity 25(5):731-744. doi:10.1016/j.immuni.2006.09.011
189. Iwama A, Osawa M, Hirasawa R, Uchiyama N, Kaneko S, Onodera M, Shibuya K, Shibuya A, Vinson C, Tenen DG, Nakauchi H (2002) Reciprocal roles for CCAAT/enhancer binding protein (C/EBP) and PU.1 transcription factors in Langerhans cell commitment. J Exp Med 195(5):547-558
190. Guerzoni C, Bardini M, Mariani SA, Ferrari-Amorotti G, Neviani P, Panno ML, Zhang Y, Martinez R, Perrotti D, Calabretta B (2006) Inducible activation of CEBPB, a gene negatively regulated by BCR/ABL, inhibits proliferation and promotes differentiation of BCR/ABL-expressing cells. Blood 107(10):4080-4089. doi:10.1182/blood-2005-08-3181
191. 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(2):460-466
192. 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 beta c gene. J Immunol 163(5):2674-2680
193. Kusmartsev S, Nagaraj S, Gabrilovich DI (2005) Tumor-associated CD8+ T cell tolerance induced by bone marrow-derived immature myeloid cells. J Immunol 175(7):4583-4592
194. Gabrilovich DI, Velders MP, Sotomayor EM, Kast WM (2001) Mechanism of immune dysfunction in cancer mediated by immature Gr-1(+) myeloid cells. J Immunol 166(9): 5398-5406
195. 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(18):6713-6721
196. Liu C, Yu S, Kappes J, Wang J, Grizzle WE, Zinn KR, Zhang HG (2007) Expansion of spleen myeloid suppressor cells represses NK cell cytotoxicity in tumor bearing host. Blood 109(10):4336-4342
197. Gigante M, Gesualdo L, Ranieri E (2012) TGF-beta: a master switch in tumor immunity. Curr Pharm Des 18(27):4126-4134
198. Li MO, Flavell RA (2008) TGF-beta: a master of all T cell trades. Cell 134(3):392-404. doi:10.1016/j.cell.2008.07.025
199. Young MR, Wright MA, Matthews JP, Malik I, Prechel M (1996) Suppression of T cell proliferation by tumor-induced granulocyte-macrophage progenitor cells producing transforming growth factor-beta and nitric oxide. J Immunol 156:1916-1922
200. Beck C, Schreiber K, Schreiber H, Rowley DA (2003) C-kit+FcR+ myelocytes are increased in cancer and prevent the proliferation of fully cytolytic T cells in the presence of immune serum. Eur J Immunol 33(1):19-28
201. Li H, Han Y, Guo Q, Zhang M, Cao X (2009) Cancer-expanded myeloid-derived suppressor cells induce anergy of NK cells through membrane-bound TGF-beta 1. J Immunol 182(1): 240-249
202. Rodrigues JC, Gonzalez GC, Zhang L, Ibrahim G, Kelly JJ, Gustafson MP, Lin Y, Di-etz AB, Forsyth PA, Yong VW, Parney IF (2010) Normal human monocytes exposed to glioma cells acquire myeloid-derived suppressor cell-like properties. Neuro-oncology 12(4): 351-365. doi:10.1093/neuonc/nop023
203. Chikamatsu K, Sakakura K, Toyoda M, Takahashi K, Yamamoto T, Masuyama K (2012) Immunosuppressive activity of CD14+HLA-DR-cells in squamous cell carcinoma of the head and neck. Cancer Sci 103(6):976-983. doi:10.1111/j.1349-7006.2012.02248.x
204. Kehrl JH, Roberts AB, Wakefield LM, Jakowlew S, Sporn MB, Fauci AS (1986) Transforming growth factor beta is an important immunomodulatory protein for human B lymphocytes. J Immunol 137(12):3855-3860
205. Morris DR, Kuepfer CA, Ellingsworth LR, Ogawa Y, Rabinovitch PS (1989) Transforming growth factor-beta blocks proliferation but not early mitogenic signaling events in T-lymphocytes. Exp Cell Res 185(2):529-534
206. Stoeck M, Miescher S, MacDonald HR, Von Fliedner V (1989) Transforming growth factors beta slow down cell-cycle progression in a murine interleukin-2 dependent T cell line. J Cell Physiol 141(1):65-73
207. Wolfraim LA, Walz TM, James Z, Fernandez T, Letterio JJ (2004) p21Cip1 and p27Kip1 act in synergy to alter the sensitivity of naive T cells to TGF-beta-mediated G1 arrest through modulation of IL-2 responsiveness. J Immunol 173(5):3093-3102
208. Brabletz T, Pfeuffer I, Schorr E, Siebelt F, Wirth T, Serfling E (1993) Transforming growth factor beta 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(2):1155-1162
209. Becker C, Fantini MC, Neurath MF (2006) TGF-beta as a T cell regulator in colitis and colon cancer. Cytokine Growth Factor Rev 17(1-2):97-106
210. Centuori SM, Trad M, LaCasse CJ, Alizadeh D, Larmonier CB, Hanke NT, Kartch-ner J, Janikashvili N, Bonnotte B, Larmonier N, Katsanis E (2012) Myeloid-derived suppressor cells from tumor-bearing mice impair TGF-beta-induced differentiation of CD4+CD25+FoxP3+ Tregs from CD4+CD25-FoxP3-T cells. J Leukoc Biol 92(5): 987-997. doi:10.1189/jlb.0911465
211. Wu G, Morris SM, Jr. (1998) Arginine metabolism: nitric oxide and beyond. Biochem J 336 (Pt 1):1-17
212. Bogdan C (2001) Nitric oxide and the immune response. Nat Immunol 2(10):907-916
213. Rodriguez PC, Quiceno DG, Zabaleta J, Ortiz B, Zea AH, Piazuelo MB, Delgado A, Correa P, Brayer J, Sotomayor EM, Antonia S, Ochoa JB, Ochoa AC (2004) Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T cell receptor expression and antigen-specific T cell responses. Cancer Res 64(16):5839-5849
214. Baniyash M (2004) TCR zeta-chain downregulation: curtailing an excessive inflammatory immune response. Nat Rev Immunol 4(9):675-687
215. 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(6-7):614-634. doi:10.3109/08820139.2012.680634
216. Rodriguez PC, Quiceno DG, Ochoa AC (2007) L-arginine availability regulates T-lymphocyte cell-cycle progression. Blood 109(4):1568-1573. doi:10.1182/blood-2006-06-031856
217. 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(9):5198-5204. doi:10.4049/jimmunol.1001224
218. Fischer TA, Palmetshofer A, Gambaryan S, Butt E, Jassoy C, Walter U, Sopper S, Lohmann SM (2001) Activation of cGMP-dependent protein kinase Ibeta inhibits interleukin 2 release and proliferation of T cell receptor-stimulated human peripheral T cells. J Biol Chem 276(8):5967-5974
219. Duhe RJ, Evans GA, Erwin RA, Kirken RA, Cox GW, Farrar WL (1998) Nitric oxide and thiol redox regulation of Janus kinase activity. Proc Natl Acad Sci U S A 95(1):126-131
220. Bingisser RM, Tilbrook PA, Holt PG, Kees UR (1998) Macrophage-derived nitric oxide regulates T cell activation via reversible disruption of the Jak3/STAT5 signaling pathway. J Immunol 160(12):5729-5734
221. Pericle F, Pinto L, Hicks S, Kirken RA, Sconocchia G, Rusnak J, Dolan MJ, Sherear GM, Segal D (1998) HIV-1 infection induces a selective reduction in STAT5 protein expression. J Immunol 160:28-31
222. Pericle F, Kirken RA, Bronte V, Sconocchia G, DaSilva L, Segal DM (1997) Immunocom-promised tumor-bearing mice show a selective loss of STAT5a/b expression in T and B lymphocytes. J Immunol 159:2580-2585
223. 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(9):4809-4815
224. Mannick JB, Hausladen A, Liu L, Hess DT, Zeng M, Miao QX, Kane LS, Gow AJ, Stamler JS (1999) Fas-induced caspase denitrosylation. Science 284 (5414) :651-654
225. Munder M, Eichmann K, Moran JM, Centeno F, Soler G, Modolell M (1999) Th1/Th2-regulated expression of arginase isoforms in murine macrophages and dendritic cells. J Immunol 163(7):3771-3777
226. Currie GA, Gyure L, Cifuentes L (1979) Microenvironmental arginine depletion by macrophages in vivo. Br J Cancer 39(6):613-620
227. 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(10): 2777-2790. doi:10.1172/JCI28828
228. Brys L, Beschin A, Raes G, Ghassabeh GH, Noel W, Brandt J, Brombacher F, De Baetselier P (2005) Reactive oxygen species and 12/15-lipoxygenase contribute to the antiproliferative capacity of alternatively activated myeloid cells elicited during helminth infection. J Immunol 174(10):6095-6104
229. Bronte V, Kasic T, Gri G, Gallana K, Borsellino G, Marigo I, Battistini L, Iafrate M, Prayer-Galetti T, Pagano F, Viola A (2005) Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers. J Exp Med 201(8):1257-1268. doi:10.1084/jem.20042028
230. Bruch-Gerharz D, Schnorr O, Suschek C, Beck KF, Pfeilschifter J, Ruzicka T, Kolb-Bachofen V (2003) Arginase 1 overexpression in psoriasis: limitation of inducible nitric oxide syn-thase activity as a molecular mechanism for keratinocyte hyperproliferation. Am J Pathol 162(1):203-211
231. Bronte V, Serafini P, Mazzoni A, Segal DM, Zanovello P (2003) L-arginine metabolism in myeloid cells controls T-lymphocyte functions. Trends Immunol 24(6):302-306
232. Xia Y, Roman LJ, Masters BS, Zweier JL (1998) Inducible nitric-oxide synthase generates superoxide from the reductase domain. J Biol Chem 273(35):22635-22639
233. Xia Y, Zweier JL (1997) Superoxide and peroxynitrite generation from inducible nitric oxide synthase in macrophages. Proc Natl Acad Sci U S A 94(13):6954-6958
234. 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(1):270-278
235. Santhanam L, Lim HK, Miriel V, Brown T, Patel M, Balanson S, Ryoo S, Anderson M, Irani K, Khanday F, Di Costanzo L, Nyhan D, Hare JM, Christianson DW, Rivers R, Shoukas A, Berkowitz DE (2007) Inducible NO synthase dependent S-nitrosylation and activation of arginase1 contribute to age-related endothelial dysfunction. Circ Res 101(7):692-702. doi:10.1161/CIRCRESAHA.107.157727
236. Gmunder H, Eck HP, Droge W (1991) Low membrane transport activity for cystine in resting and mitogenically stimulated human lymphocyte preparations and human T cell clones. Eur J Biochem 201(1):113-117
237. Bannai S (1984) Transport of cystine and cysteine in mammalian cells. Biochim Biophys Acta 779(3):289-306
238. Iwata S, Hori T, Sato N, Ueda-Taniguchi Y, Yamabe T, Nakamura H, Masutani H, Yodoi J (1994) Thiol-mediated redox regulation of lymphocyte proliferation. Possible involvement of adult T cell leukemia-derived factor and glutathione in transferrin receptor expression. J Immunol 152(12):5633-5642
239. Gmunder H, Eck HP, Benninghoff B, Roth S, Droge W (1990) Macrophages regulate intracel-lular glutathione levels of lymphocytes. Evidence for an immunoregulatory role of cysteine. Cell Immunol 129(1):32-46
240. 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(1):68-77. doi:10.1158/0008-5472.CAN-09-2587
241. Otsuji M, Kimura Y, Aoe T, Okamoto Y, Saito T (1996) Oxidative stress by tumor-derived macrophages suppresses the expression of CD3 zeta chain of T cell receptor complex and antigen-specific T-cell responses. Proc Natl Acad Sci U S A 93(23):13119-13124
242. Kono K, Ressing ME, Brandt RM, Melief CJ, Potkul RK, Andersson B, Petersson M, Kast WM, Kiessling R (1996) Decreased expression ofsignal-transducing zeta chaininperipheral T cells and natural killer cells inpatients with cervical cancer. Clin Cancer Res 2(11):1825-1828
243. Kono K, Salazar-Onfray F, Petersson M, Hansson J, Masucci G, Wasserman K, Nakazawa T, Anderson P, Kiessling R (1996) Hydrogen peroxide secreted by tumor-derived macrophages down-modulates signal-transducing zeta molecules and inhibits tumor-specific T cell-and natural killer cell-mediated cytotoxicity. Eur J Immunol 26(6):1308-1313
244. 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(1):167-181. doi:10.1189/jlb.0311177
245. 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(2):311-317. doi:10.1189/jlb.0310162
246. Kusmartsev S, Nefedova Y, Yoder D, Gabrilovich DI (2004) Antigen-specific inhibition of CD8+ T cell response by immature myeloid cells in cancer is mediated by reactive oxygen species. J Immunol 172(2):989-999
247. Lu T, Gabrilovich DI (2012) Molecular pathways: tumor-infiltrating myeloid cells and reactive oxygen species in regulation of tumor microenvironment. Clin Cancer Res 18(18):4877-4882. doi:10.1158/1078-0432.CCR-11-2939
248. Bedard K, Krause KH (2007) The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87(1):245-313. doi:10.1152/physrev.00044.2005
249. Andrew PJ, Mayer B (1999) Enzymatic function of nitric oxide synthases. Cardiovasc Res 43(3):521-531
250. Tsai P, Weaver J, Cao GL, Pou S, Roman LJ, Starkov AA, Rosen GM (2005) L-arginine regulates neuronal nitric oxide synthase production of superoxide and hydrogen peroxide. Biochem Pharmacol 69(6):971-979
251. Que LG, George SE, Gotoh T, Mori M, Huang YC (2002) Effects of arginase isoforms on NO production by nNOS. Nitric Oxide 6(1):1-8
252. Alvarez B, Radi R (2003) Peroxynitrite reactivity with amino acids and proteins. Amino Acids 25(3-4):295-311. doi:10.1007/s00726-003-0018-8
253. Nagaraj S, Gupta K, Pisarev V, Kinarsky L, Sherman S, Kang L, Herber DL, Schneck J, Gabrilovich DI (2007) Altered recognition of antigen is a mechanism of CD8(+) T cell tolerance in cancer. Nat Med 13(7):828-835
254. Lu T, Ramakrishnan R, Altiok S, Youn JI, Cheng P, Celis E, Pisarev V, Sherman S, Sporn MB, Gabrilovich D (2011) Tumor-infiltrating myeloid cells induce tumor cell resistance to cytotoxic T cells in mice. J Clin Invest 121(10):4015-4029. doi:10.1172/JCI45862
255. Mahnke K, Qian Y, Knop J, Enk AH (2003) Induction of CD4+/CD25+regulatory T cells by targeting of antigens to immature dendritic cells. Blood 101(12):4862-4869
256. MacDonald KP, Rowe V, Clouston AD, Welply JK, Kuns RD, Ferrara JL, Thomas R, Hill GR (2005) Cytokine expanded myeloid precursors function as regulatory antigen-presenting cells and promote tolerance through IL-10-producing regulatory T cells. J Immunol 174(4): 1841-1850
257. Ghiringhelli F, Puig PE, Roux S, Parcellier A, Schmitt E, Solary E, Kroemer G, Martin F, Chauffert B, Zitvogel L (2005) Tumor cells convert immature myeloid dendritic cells into TGF-beta-secreting cells inducing CD4+CD25+ regulatory T cell proliferation. J Exp Med 202(7):919-929
258. 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(13):5439-5449. doi:10.1158/0008-5472.CAN-07-6621
259. Pan PY, Ma G, Weber KJ, Ozao-Choy J, Wang G, Yin B, Divino CM, Chen SH (2010) Immune stimulatory receptor CD40 is required for T cell suppression and T regulatory cell activation mediated by myeloid-derived suppressor cells in cancer. Cancer Res 70(1):99-108. doi:10.1158/0008-5472.CAN-09-1882
260. Hoechst B, Ormandy LA, Ballmaier M, Lehner F, Kruger C, Manns MP, Greten TF, Korangy F (2008) A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4(+)CD25(+)Foxp3(+) T cells. Gastroenterology 135(1):234-243. doi:10.1053/j.gastro.2008.03.020
261. 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(24):6532-6541. doi:10.1182/blood-2010-11-317321
262. Yang R, Cai Z, Zhang Y, Yutzy WHIV, Roby KF, Roden RBS (2006) CD80 in immune suppression by mouse ovarian carcinoma-associated Gr-1+CD11b+ myeloid cells. Cancer Res 66(13):6807-6815. doi:10.1158/0008-5472.can-05-3755
263. Mellor AL, Munn DH (2004) IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol 4(10):762-774
264. Fujimura T, Ring S, Umansky V, Mahnke K, Enk AH (2012) Regulatory T cells stimulate B7-H1 expression in myeloid-derived suppressor cells in ret melanomas. J Invest Dermatol 132(4):1239-1246. doi:10.1038/jid.2011.416
265. Schlecker E, Stojanovic A, Eisen C, Quack C, Falk CS, Umansky V, Cerwenka A (2012) Tumor-infiltrating monocytic myeloid-derived suppressor cells mediate CCR5-dependent recruitment of regulatory T cells favoring tumor growth. J Immunol 189(12):5602-5611. doi:10.4049/jimmunol.1201018
266. Terabe M, Berzofsky JA (2007) NKT cells in immunoregulation of tumor immunity: a new immunoregulatory axis. Trends Immunol 28(11):491-496. doi:10.1016/j.it.2007.05.008
267. Ostrand-Rosenberg S, Sinha P, Beury DW, Clements VK (2012) Cross-talk between myeloid-derived suppressor cells (MDSC), macrophages, and dendritic cells enhances tumor-induced immune suppression. Semin Cancer Biol 22(4):275-281. doi:10.1016/j. semcancer.2012.01.011
268. Nagaraj S, Nelson A, Youn JI, Cheng P, Quiceno D, Gabrilovich DI (2012) Antigen-specific CD4(+) T cells regulate function of myeloid-derived suppressor cells in cancer via retrograde MHC class II signaling. Cancer Res 72(4):928-938. doi:10.1158/0008-5472.CAN-11-2863
269. Young MR, Wright MA, Lozano Y, Prechel MM, Benefield J, Leonetti JP, Collins SL, Petruzzelli GJ (1997) Increased recurrence and metastasis in patients whose primary head and neck squamous cell carcinomas secreted granulocyte-macrophage colony-stimulating factor and contained CD34+ natural suppressor cells. Int J Cancer 74(1):69-74
270. Pak AS, Wright MA, Matthews JP, Collins SL, Petruzzelli GJ, Young MRI (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(1):95-103
271. 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(5):663-669
272. 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(1):678-689
273. 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(8):2254-2265. doi:10.1182/blood-2010-12-325753
274. 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(2):107-115. doi:10.1097/CJI.0b013e318242169f
275. 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(1):49-59. doi:10.1007/s00262-008-0523-4
276. Trellakis S, Bruderek K, Hutte J, Elian M, Hoffmann TK, Lang S, Brandau S (2013) Granulo-cytic 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(3):328-336. doi:10.1177/1753425912463618
277. 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(8):3044-3048. doi:10.1158/0008-5472.CAN-04-4505
278. Filipazzi P, Valenti R, Huber V, Pilla L, Canese P, Iero M, Castelli C, Mariani L, Parmi-ani G, Rivoltini L (2007) Identification of a new subset of myeloid suppressor cells in peripheral blood of melanoma patients with modulation by a granulocyte-macrophage colony-stimulation factor-based antitumor vaccine. J Clin Oncol 25(18):2546-2553. doi:10.1200/JCO.2006.08.5829
279. Mandruzzato S, Solito S, Falisi E, Francescato S, Chiarion-Sileni V, Mocellin S, Zanon A, Rossi CR, Nitti D, Bronte V, Zanovello P (2009) IL4Ralpha+myeloid-derived suppressor cell expansionincancer patients. JImmunol 182(10):6562-6568. doi:10.4049/jimmunol.0803831
280. Poschke I, Mougiakakos D, Hansson J, Masucci GV, Kiessling R (2010) Immature immuno-suppressive CD14+HLA-DR-/low cells in melanoma patients are Stat3hi and overexpress CD80, CD83, and DC-sign. Cancer Res 70(11):4335-4345. doi:10.1158/0008-5472.CAN-09-3767
281. Hoechst B, Voigtlaender T, Ormandy L, Gamrekelashvili J, Zhao F, Wedemeyer H, Lehner F, Manns MP, Greten TF, Korangy F (2009) Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKp30 receptor. Hepatology 50(3):799-807. doi:10.1002/hep.23054
282. 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(5):1109-1119. doi:10.1002/ijc.26123
283. 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. doi:10.1038/nm.2883
284. Gabrilovich DI, Ostrand-Rosenberg S, Bronte V (2012) Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol 12(4):253-268. doi:10.1038/nri3175
285. Young MR, Wright MA, Vellody K, Lathers DM (1999) Skewed differentiation of bone marrow CD34+ cells of tumor bearers from dendritic toward monocytic cells, and the redirection of differentiation toward dendritic cells by 1alpha, 25-dihydroxyvitamin D3. Int J Immunopharmacol 21(10):675-688
286. Walsh JE, Clark AM, Day TA, Gillespie MB, Young MR (2010) Use of alpha, 25-dihydroxyvitamin D3 treatment to stimulate immune infiltration into head and neck squamous cell carcinoma. Hum Immunol 71(7):659-665. doi:10.1016/j.humimm.2010.04.008
287. Walker DD, Reeves TD, de Costa AM, Schuyler C, Young MR (2012) Immunological modulation by 1alpha, 25-dihydroxyvitamin D3 in patients with squamous cell carcinoma of the head and neck. Cytokine 58(3):448-454. doi:10.1016/j.cyto.2012.03.002
288. Ben-Shoshan M, Amir S, Dang DT, Dang LH, Weisman Y, Mabjeesh NJ (2007) 1alpha, 25-dihydroxyvitamin D3 (Calcitriol) inhibits hypoxia-inducible factor-1/vascular endothe-lial growth factor pathway in human cancer cells. Mol Cancer Ther 6(4):1433-1439. doi:10.1158/1535-7163.MCT-06-0677
289. 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(6):2514-2522. doi:10.1158/0008-5472.CAN-08-4709
290. 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(6):2148-2157. doi:10.1158/1078-0432.CCR-08-1332
291. Porta C, Paglino C, Imarisio I, Ganini C, Pedrazzoli P (2011) Immunological effects of multikinase inhibitors for kidney cancer: a clue for integration with cellular therapies? J Cancer 2:333-338
292. Choong NW, Kozloff M, Taber D, Hu HS, Wade J 3rd, Ivy P, Karrison TG, Dekker A, Vokes EE, Cohen EE (2010) Phase II study of sunitinib malate in head and neck squamous cell carcinoma. Invest New Drugs 28(5):677-683. doi:10.1007/s10637-009-9296-7
293. Fountzilas G, Fragkoulidi A, Kalogera-Fountzila A, Nikolaidou M, Bobos M, Calderaro J, Andreiuolo F, Marselos M (2010) A phase II study of sunitinib in patients with recurrent and/or metastatic non-nasopharyngeal head and neck cancer. Cancer Chemother Pharmacol 65(4):649-660. doi:10.1007/s00280-009-1070-1
294. Machiels JP, Henry S, Zanetta S, Kaminsky MC, Michoux N, Rommel D, Schmitz S, Bompas E, Dillies AF, Faivre S, Moxhon A, Duprez T, Guigay J (2010) Phase II study of sunitinib in recurrent or metastatic squamous cell carcinoma of the head and neck: GORTEC 2006-01. J Clin Oncol 28(1):21-28. doi:10.1200/JCO.2009.23.8584
295. Kao J, Packer S, Vu HL, Schwartz ME, Sung MW, Stock RG, Lo YC, Huang D, Chen SH, Cesaretti JA (2009) Phase 1 study of concurrent sunitinib and image-guided radiotherapy followed by maintenance sunitinib for patients with oligometastases: acute toxicity and preliminary response. Cancer 115(15):3571-3580. doi:10.1002/cncr.24412
296. 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(9):3526-3536. doi:10.1158/0008-5472.CAN-09-3278
297. 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(7): 856-861. doi:10.1016/j.intimp.2011.01.030
298. Zhang B, Bowerman NA, Salama JK, Schmidt H, Spiotto MT, Schietinger A, Yu P, Fu YX, Weichselbaum RR, Rowley DA, Kranz DM, Schreiber H (2007) Induced sensitization of tumor stroma leads to eradication of established cancer by T cells. J Exp Med 204(1):49-55
299. 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(18):9299-9307. doi:10.1158/0008-5472.CAN-06-1690
300. Itoh S, Matsui K, Furuta I, Takano Y (2003) Immunohistochemical study on overexpression of cyclooxygenase-2insquamous cell carcinomaof the oral cavity: its importanceasaprognostic predictor. Oral Oncol 39(8):829-835
301. Ochoa AC, Zea AH, Hernandez C, Rodriguez PC (2007) Arginase, prostaglandins, and myeloid-derived suppressor cells in renal cell carcinoma. Clin Cancer Res 13(2 Pt 2):721s-726s. doi:10.1158/1078-0432.CCR-06-2197
302. Wirth LJ, Haddad RI, Lindeman NI, Zhao X, Lee JC, Joshi VA, Norris CM, Jr., Posner MR (2005) Phase I study of gefitinib plus celecoxib in recurrent or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol 23(28):6976-6981. doi:10.1200/JCO.2005.02.4182
303. Kao J, Genden EM, Chen CT, Rivera M, Tong CC, Misiukiewicz K, Gupta V, Gurudutt V, Teng M, Packer SH (2011) Phase 1 trial of concurrent erlotinib, celecoxib, and reirradiation for recurrent head and neck cancer. Cancer 117(14):3173-3181. doi:10.1002/cncr.25786
304. Dajani EZ, Islam K (2008) Cardiovascular and gastrointestinal toxicity of selective cyclo-oxygenase-2 inhibitors in man. J Physiol Pharmacol 59(Suppl 2):S117-S133
305. Solomon SD, McMurray JJ, Pfeffer MA, Wittes J, Fowler R, Finn P, Anderson WF, Zauber A, Hawk E, Bertagnolli M (2005) Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 352(11):1071-1080. doi:10.1056/NEJMoa050405
306. Huang WF, Hsiao FY, Wen YW, Tsai YW (2006) Cardiovascular events associated with the use of four nonselective NSAIDs (etodolac, nabumetone, ibuprofen, or naproxen) versus a cyclooxygenase-2 inhibitor (celecoxib): a population-based analysis in Taiwanese adults. Clin Ther 28(11):1827-1836. doi:10.1016/j.clinthera.2006.11.009