Myeloid-derived suppressor cells: Mechanisms of action and recent advances in their role in transplant tolerance

Frontiers in Immunology

Volumn 3, Issue JUL, 2012, Pages

  Dilek, Nahzli ^a,b   de Silly, Romain Vuillefroy ^a,c   Blancho, Gilles ^a,c,d   Vanhove, Bernard ^a,c,d  

^a Centre National de la Recherche Scientifique   (France)

^b Effimune SAS   (France)

^c UNIVERSITÉ DE NANTES   (France)

^d NANTES UNIVERSITY HOSPITAL   (France)

Author keywords

Immune suppression; Myeloid suppressor cells; Tolerance; Transplantation

Indexed keywords

EID: 84874211785     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2012.00208     Document Type: Review

References (92)

1. Adeegbe, D., Serafini, P., Bronte, V., Zoso, A., Ricordi, C., and Inverardi, L. (2010). In vivo induction of myeloid suppressor cells and CD4+Foxp3+ T regulatory cells prolongs skin allo-graft survival in mice. Cell Transplant. 20, 941-954.
2. Agostinelli, E., and Seiler, N. (2006). Non-irradiation-derived reactive oxygen species (ROS) and cancer: therapeutic implications. Amino Acids 31, 341-355.
3. Almand, B., Clark, J. I., Nikitina, E., van Beynen, J., English, N. R., Knight, S. C., Carbone, D. P., and Gabrilovich, D. I. (2001). Increased production of immature myeloid cells in cancer patients: a mechanism of immuno-suppression in cancer. J. Immunol. 166, 678-689.
4. Angelini, G., Gardella, S., Ardy, M., Ciriolo, M. R., Filomeni, G., Di Trapani, G., Clarke, F., Sitia, R., and Rubartelli, A. (2002). Antigen-presenting dendritic cells provide the reducing extracellular microenviron-ment required for T lymphocyte activation. Proc. Natl. Acad. Sci. U.S.A. 99, 1491-1496.
5. Bannai, S. (1984). Transport of cys-tine and cysteine in mammalian cells. Biochim. Biophys. Acta 779, 289-306.
6. Bingisser, R. M., Tilbrook, P. A., Holt, P. G., and Kees, U. R. (1998). Macrophage-derived nitric oxide regulates T cell activation via reversible disruption of the Jak3/STAT5 signaling pathway. J. Immunol. 160, 5729-5734.
7. Bobe, P., Benihoud, K., Grand-jon, D., Opolon, P., Pritchard, L. L., and Huchet, R. (1999). Nitric oxide mediation of active immunosuppression associated with graft-versus-host reaction. Blood 94, 1028-1037.
8. Brito, C., Naviliat, M., Tiscornia, A. C., Vuillier, F., Gualco, G., Dighiero, G., Radi, R., and Cayota, A. M. (1999). Peroxynitrite inhibits T lymphocyte activation and proliferation by promoting impairment of tyrosine phosphorylation and peroxynitrite-driven apoptotic death. J. Immunol. 162, 3356-3366.
9. Bronte, V., Apolloni, E., Cabrelle, A., Ronca, R., Serafini, P., Zam-boni, P., Restifo, N. P., and Zanovello, P. (2000). Identification of a CD11b(+)/Gr-1(+)/CD31(+) myeloid progenitor capable of activating or suppressing CD8(+) T cells. Blood 96, 3838-3846.
10. Bronte, V., Chappell, D. B., Apolloni, E., Cabrelle, A., Wang, M., Hwu, P., and Restifo, N. P. (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.
11. Bronte, V., Kasic, T., Gri, G., Gallana, K., Borsellino, G., Marigo, I., Bat-tistini, L., Iafrate, M., Prayer-Galetti, T., Pagano, F., and Viola, A. (2005). Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers. J. Exp. Med. 201, 1257-1268.
12. Bronte, V., Serafini, P., Mazzoni, A., Segal, D. M., and Zanovello, P. (2003). L-arginine metabolism in myeloid cells controls T-lymphocyte functions. Trends Immunol. 24, 302-306.
13. Bronte, V., Wang, M., Overwijk, W. W., Surman, D. R., Pericle, F., Rosenberg, S. A., and Restifo, N. P. (1998). Apoptotic death of CD8+ T lymphocytes after immunization: induction of a suppressive population of Mac-1+/Gr-1+ cells. J. Immunol. 161, 5313-5320.
14. Bronte, V., and Zanovello, P. (2005). Regulation of immune responses by L-arginine metabolism. Nat. Rev. Immunol. 5, 641-654.
15. Bunt, S. K., Yang, L., Sinha, P., Clements, V. K., Leips, J., and Ostrand-Rosenberg, S. (2007). Reduced inflammation in the tumor microen-vironment delays the accumulation of myeloid-derived suppressor cells and limits tumor progression. Cancer Res. 67, 10019-10026.
16. Cauley, L. S., Miller, E. E., Yen, M., and Swain, S. L. (2000). Superantigen-induced CD4 T cell tolerance mediated by myeloid cells and IFN-gamma. J. Immunol. 165, 6056-6066.
17. Chalmin, F., Ladoire, S., Mignot, G., Vincent, J., Bruchard, M., Remy-Martin, J. P., 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., Rebe, C., and Ghiringhelli, F. (2010). Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppres-sive function of mouse and human myeloid-derived suppressor cells. J. Clin. Invest. 120, 457-471.
18. Corzo, C. A., Cotter, M. J., Cheng, P., Cheng, F., Kusmartsev, S., Sotomayor, E., Padhya, T., McCaffrey, T. V., McCaffrey, J. C., and Gabrilovich, D. I. (2009). Mechanism regulating reactive oxygen species in tumor-induced myeloid-derived suppressor cells. J. Immunol. 182, 5693-5701.
19. Cripps, J. G., Wang, J., Maria, A., Blumenthal, I., and Gorham, J. D. (2010). Type 1 T helper cells induce the accumulation of myeloid-derived suppressor cells in the inflamed Tgfb1 knockout mouse liver. Hepatology 52, 1350-1359.
20. De Wilde, V., Van Rompaey, N., Hill, M., Lebrun, J. F., Lemaitre, P., Lhomme, F., Kubjak, C., Vokaer, B., Old-enhove, G., Charbonnier, L. M., Cuturi, M. C., Goldman, M., and Le Moine, A. (2009). Endotoxin-induced myeloid-derived suppressor cells inhibit alloimmune responses via heme oxygenase-1. Am. J. Transplant. 9, 2034-2047.
21. Dugast, A. S., Haudebourg, T., Coulon, F., Heslan, M., Haspot, F., Poirier, N., Vuillefroy de Silly, R., Usal, C., Smit, H., Martinet, B., Thebault, P., Renaudin, K., and Vanhove, B. (2008). Myeloid-derived suppressor cells accumulate in kidney allograft tolerance and specifically suppress effector T cell expansion. J. Immunol. 180, 7898-7906.
22. Ezernitchi, A. V., Vaknin, I., Cohen-Daniel, L., Levy, O., Manaster, E., Halabi, A., Pikarsky, E., Shapira, L., and Baniyash, M. (2006). TCR zeta down-regulation under chronic inflammation is mediated by myeloid suppressor cells differentially distributed between various lymphatic organs. J. Immunol. 177, 4763- 4772.
23. Gabrilovich, D. (2004). Mechanisms and functional significance of tumour-induced dendritic-cell defects. Nat. Rev. Immunol. 4, 941-952.
24. Gabrilovich, D. I. (2007). Molecular mechanisms and therapeutic reversal of immune suppression in cancer. Curr. Cancer Drug Targets 7, 1.
25. Gabrilovich, D. I., Velders, M. P., Sotomayor, E. M., and Kast, W. M. (2001). Mechanism of immune dysfunction in cancer mediated by immature Gr-1+ myeloid cells. J. Immunol. 166, 5398-5406.
26. Gallina, G., Dolcetti, L., Serafini, P., De Santo, C., Marigo, I., Colombo, M. P., Basso, G., Brombacher, F., Bor-rello, I., Zanovello, P., Bicciato, S., and Bronte, V. (2006). Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells. J. Clin. Invest. 116, 2777-2790.
27. Garcia, M. R., Ledgerwood, L., Yang, Y., Xu, J., Lal, G., Burrell, B., Ma, G., Hashimoto, D., Li, Y., Boros, P., Grisotto, M., van Rooijen, N., Mate-sanz, R., Tacke, F., Ginhoux, F., Ding, Y., Chen, S. H., Randolph, G., Merad, M., Bromberg, J. S., and Ochando, J. C. (2010). Monocytic suppressive cells mediate cardiovascular transplantation tolerance in mice. J. Clin. Invest. 120, 2486-2496.
28. Ghansah, T., Paraiso, K. H., Highfill, S., Desponts, C., May, S., McIn-tosh, J. K., Wang, J. W., Ninos, J., Brayer, J., Cheng, F., Sotomayor, E., and Kerr, W. G. (2004). Expansion of myeloid suppressor cells in SHIP-deficient mice represses allogeneic T cell responses. J. Immunol. 173, 7324-7330.
29. Goni, O., Alcaide, P., and Fresno, M. (2002). Immunosuppression during acute Trypanosoma cruzi infection: involvement of Ly6G (Gr1(+)) CD11b(+)immature myeloid suppressor cells. Int. Immunol. 14, 1125-1134.
30. Hanson, E. M., Clements, V. K., Sinha, P., Ilkovitch, D., and Ostrand-Rosenberg, S. (2009). Myeloid-derived suppressor cells down-regulate L-selectin expression on CD4+ and CD8+ T cells. J. Immunol. 183, 937-944.
31. Harari, O., and Liao, J. K. (2004). Inhibition of MHC II gene transcription by nitric oxide and antioxidants. Curr. Pharm. Des. 10, 893-898.
32. Highfill, S. L., Rodriguez, P. C., Zhou, Q., Goetz, C. A., Koehn, B. H., Veen-stra, R., Taylor, P. A., Panoskaltsis-Mortari, A., Serody, J. S., Munn, D. H., Tolar, J., Ochoa, A. C., and Blazar, B. R. (2010). Bone marrow myeloid-derived suppressor cells (MDSCs) inhibit graft-versus-host disease (GVHD) via an arginase-1-dependent mechanism that is up-regulated by interleukin-13. Blood 116, 5738-5747.
33. Hock, B. D., Mackenzie, K. A., Cross, N. B., Taylor, K. G., Currie, M. J., Robinson, B. A., Simcock, J. W., and McKenzie, J. L. (2012). Renal transplant recipients have elevated frequencies of circulating myeloid-derived suppressor cells. Nephrol. Dial. Transplant. 27, 402-410.
34. Hoechst, B., Ormandy, L. A., Ballmaier, M., Lehner, F., Kruger, C., Manns, M. P., Greten, T. F., and Korangy, F. (2008). A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4(+)CD25(+)Foxp3(+) T cells. Gastroenterology 135, 234-243.
35. Huang, B., Pan, P. Y., Li, Q., Sato, A. I., Levy, D. E., Bromberg, J., Divino, C. M., and Chen, S. H. (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, 1123- 1131
36. Jia, W., Jackson-Cook, C., and Graf, M. R. (2010). Tumor-infiltrating, myeloid-derived suppressor cells inhibit T cell activity by nitric oxide production in an intracranial rat glioma + vaccination model. J. Neuroimmunol. 223, 20-30
37. Kusmartsev, S., Cheng, F., Yu, B., Nefe-dova, Y., Sotomayor, E., Lush, R., and 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.
38. Kusmartsev, S., Nagaraj, S., and Gabrilovich, D. I. (2005). Tumor-associated CD8+ T cell tolerance induced by bone marrow-derived immature myeloid cells. J. Immunol. 175, 4583-4592.
39. Kusmartsev, S., Nefedova, Y., Yoder, D., and Gabrilovich, D. I. (2004). Antigen-specific inhibition of CD8+ T cell response by immature myeloid cells in cancer is mediated by reactive oxygen species. J. Immunol. 172, 989-999.
40. Kusmartsev, S. A., Li, Y., and Chen, S. H. (2000). Gr-1+ myeloid cells derived from tumor-bearing mice inhibit primary T cell activation induced through CD3/CD28 costimulation. J. Immunol. 165, 779-785.
41. Levey, D. L., and Srivastava, P. K. (1995). T cells from late tumor-bearing mice express normal levels of p56lck, p59fyn, ZAP-70, and CD3 zeta despite suppressed cytolytic activity. J. Exp. Med. 182, 1029-1036.
42. Li, H., Han, Y., Guo, Q., Zhang, M., and Cao, X. (2009). Cancer-expanded myeloid-derived suppressor cells induce anergy of NK cells through membrane-bound TGF-beta 1. J. Immunol. 182, 240-249.
43. Li, Q., Pan, P. Y., Gu, P., Xu, D., and Chen, S. H. (2004). Role of immature myeloid Gr-1+ cells in the development of antitumor immunity. Cancer Res. 64, 1130-1139.
44. Liu, Q., Sasaki, T., Kozieradzki, I., Wake-ham, A., Itie, A., Dumont, D. J., and Penninger, J. M. (1999). SHIP is a negative regulator of growth factor receptor-mediated PKB/Akt activation and myeloid cell survival. Genes Dev. 13, 786-791.
45. Lu, T., Ramakrishnan, R., Altiok, S., Youn, J. I., Cheng, P., Celis, E., Pisarev, V., Sherman, S., Sporn, M. B., and Gabrilovich, D. (2011). Tumor-infiltrating myeloid cells induce tumor cell resistance to cytotoxic T cells in mice. J. Clin. Invest. 121, 4015-4029.
46. Maier, T., Holda, J. H., and Claman, H. N. (1989). Natural suppressor cells. Prog. Clin. Biol. Res. 288, 235-244.
47. Mantovani, G., Maccio, A., Madeddu, C., Mura, L., Gramignano, G., Lusso, M. R., Massa, E., Mocci, M., and Serpe, R. (2003). Antioxidant agents are effective in inducing lymphocyte progression through cell cycle in advanced cancer patients: assessment of the most important laboratory indexes of cachexia and oxidative stress. J. Mol. Med. (Berl.) 81, 664-673.
48. Marigo, I., Bosio, E., Solito, S., Mesa, C., Fernandez, A., Dolcetti, L., Ugel, S., Sonda, N., Bicciato, S., Falisi, E., Calabrese, F., Basso, G., Zanov-ello, P., Cozzi, E., Mandruzzato, S., and Bronte, V. (2010). Tumor-induced tolerance and immune suppression depend on the C/EBPbeta transcription factor. Immunity 32, 790-802.
49. Markiewski, M. M., DeAngelis, R. A., Benencia, F., Ricklin-Lichtsteiner, S. K., Koutoulaki, A., Gerard, C., Coukos, G., and Lambris, J. D. (2008). Modulation of the antitumor immune response by complement. Nat. Immunol. 9, 1225-1235.
50. Marshall, M. A., Jankovic, D., Maher, V. E., Sher, A., and Berzofsky, J. A. (2001). Mice infected with Schis-tosoma mansoni develop a novel non-T-lymphocyte suppressor population which inhibits virus-specific CTL induction via a soluble factor. Microbes Infect. 3, 1051-1061.
51. Mazzoni, A., Bronte, V., Visintin, A., Spitzer, J. H., Apolloni, E., Ser-afini, P., Zanovello, P., and Segal, D. M. (2002). Myeloid suppressor lines inhibit T cell responses by an NO-dependent mechanism. J. Immunol. 168, 689-695.
52. Melani, C., Chiodoni, C., Forni, G., and Colombo, M. P. (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, 2138-2145.
53. Mellstedt, H., Fagerberg, J., Frodin, J. E., Henriksson, L., Hjelm-Skoog, A. L., Liljefors, M., Ragnham-mar, P., Shetye, J., and Osterborg, A. (1999). Augmentation of the immune response with granulocyte-macrophage colony-stimulating factor and other hematopoietic growth factors. Curr. Opin. Hematol. 6, 169-175.
54. Mencacci, A., Montagnoli, C., Bacci, A., Cenci, E., Pitzurra, L., Spreca, A., Kopf, M., Sharpe, A. H., and Romani, L. (2002). CD80+Gr-1+ myeloid cells inhibit development of antifungal Th1 immunity in mice with candidiasis. J. Immunol. 169, 3180-3190.
55. Mills, C. D., Shearer, J., Evans, R., and Caldwell, M. D. (1992). Macrophage arginine metabolism and the inhibition or stimulation of cancer. J. Immunol. 149, 2709-2714.
56. Movahedi, K., Guilliams, M., Van den Bossche, J., Van den Bergh, R., Gyse-mans, C., Beschin, A., De Baetselier, P., and Van Ginderachter, J. A. (2008). Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity. Blood 111, 4233-4244.
57. Nagaraj, S., Gupta, K., Pisarev, V., Kinarsky, L., Sherman, S., Kang, L., Herber, D. L., Schneck, J., and Gabrilovich, D. I. (2007). Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer. Nat. Med. 13, 828-835.
58. Nagaraj, S., Schrum, A. G., Cho, H. I., Celis, E., and Gabrilovich, D. I. (2010). Mechanism of T cell tolerance induced by myeloid-derived suppressor cells. J. Immunol. 184, 3106-3116.
59. Nefedova, Y., Huang, M., Kusmart-sev, S., Bhattacharya, R., Cheng, P., Salup, R., Jove, R., and Gabrilovich, D. (2004). Hyperactivation of STAT3 is involved in abnormal differentiation of dendritic cells in cancer. J. Immunol. 172, 464-474.
60. Obermajer, N., Muthuswamy, R., Lesnock, J., Edwards, R. P., and Kalinski, P. (2011). Positive feedback between PGE2 and COX2 redirects the differentiation of human dendritic cells toward stable myeloid-derived suppressor cells. Blood 118, 5498-5505.
61. Ohm, J. E., and Carbone, D. P. (2001). VEGF as a mediator of tumor-associated immunodeficiency. Immunol. Res. 23, 263-272.
62. Pak, A. S., Wright, M. A., Matthews, J. P., Collins, S. L., Petruzzelli, G. J., and Young, M. R. (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. Pan, P. Y., Wang, G. X., Yin, B., Ozao, J., Ku, T., Divino, C. M., and Chen, S. H. (2008). Reversion of immune tolerance in advanced malignancy: modulation of myeloid-derived suppressor cell development by blockade of stem-cell factor function. Blood 111, 219-228.
64. Paraiso, K. H., Ghansah, T., Costello, A., Engelman, R. W., and Kerr, W. G. (2007). Induced SHIP deficiency expands myeloid regulatory cells and abrogates graft-versus-host disease. J. Immunol. 178, 2893-2900.
65. Rivoltini, L., Carrabba, M., Huber, V., Castelli, C., Novellino, L., Dalerba, P., Mortarini, R., Arancia, G., Ani-chini, A., Fais, S., and Parmiani, G. (2002). Immunity to cancer: attack and escape in T lymphocyte-tumor cell interaction. Immunol. Rev. 188, 97-113.
66. Rodriguez, P. C., Quiceno, D. G., and Ochoa, A. C. (2007). L-arginine availability regulates T-lymphocyte cell-cycle progression. Blood 109, 1568-1573.
67. Rodriguez, P. C., Quiceno, D. G., Zabaleta, J., Ortiz, B., Zea, A. H., Piazuelo, M. B., Delgado, A., Cor-rea, P., Brayer, J., Sotomayor, E. M., Antonia, S., Ochoa, J. B., and Ochoa, A. C. (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, 5839-5849.
68. Rodriguez, P. C., Zea, A. H., Culotta, K. S., Zabaleta, J., Ochoa, J. B., and Ochoa, A. C. (2002). Regulation of T cell receptor CD3zeta chain expression by L-arginine. J. Biol. Chem. 277, 21123-21129.
69. Sauer, H., Wartenberg, M., and Hes-cheler, J. (2001). Reactive oxygen species as intracellular messengers during cell growth and differentiation. Cell Physiol. Biochem. 11, 173-186.
70. Schmidt-Wolf, I. G., Dejbakhsh-Jones, S., Ginzton, N., Greenberg, P., and Strober, S. (1992). T-cell subsets and suppressor cells in human bone marrow. Blood 80, 3242-3250.
71. Schmielau, J., and Finn, O. J. (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, 4756-4760.
72. Serafini, P., Borrello, I., and Bronte, V. (2006). Myeloid suppressor cells in cancer: recruitment, pheno-type, properties, and mechanisms of immune suppression. Semin. Cancer Biol. 16, 53-65.
73. Serafini, P., Mgebroff, S., Noonan, K., and Borrello, I. (2008). Myeloid-derived suppressor cells promote cross-tolerance in B-cell lymphoma by expanding regulatory T cells. Cancer Res. 68, 5439-5449.
74. Sinha, P., Chornoguz, O., Clements, V. K., Artemenko, K. A., Zubarev, R. A., and Ostrand-Rosenberg, S. (2011). Myeloid-derived suppressor cells express the death receptor Fas and apoptose in response to T cell-expressed FasL. Blood 117, 5381- 5390.
75. Sinha, P., Clements, V. K., Fulton, A. M., and Ostrand-Rosenberg, S. (2007a). Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells. Cancer Res. 67, 4507-4513.
76. Sinha, P., Clements, V. K., Bunt, S. K., Albelda, S. M., and Ostrand-Rosenberg, S. (2007b). Cross-talk between myeloid-derived suppressor cells and macrophages subverts tumor immunity toward a type 2 response. J. Immunol. 179, 977-983.
77. Solheim, J. C., Reber, A. J., Ashour, A. E., Robinson, S., Futakuchi, M., Kurz, S. G., Hood, K., Fields, R. R., Shafer, L. R., Cornell, D., Sutjipto, S., Zurawski, S., LaFace, D. M., Singh, R. K., and Talmadge, J. E. (2007). Spleen but not tumor infiltration by dendritic and T cells is increased by intravenous adenovirus-Flt3 lig-and injection. Cancer Gene Ther. 14, 364-371.
78. Srivastava, M. K., Sinha, P., Clements, V. K., Rodriguez, P., and Ostrand-Rosenberg, S. (2010). Myeloid-derived suppressor cells inhibit T-cell activation by depleting cystine and cysteine. Cancer Res. 70, 68-77.
79. Strober, S. (1984). Natural suppressor (NS) cells, neonatal tolerance, and total lymphoid irradiation: exploring obscure relationships. Annu. Rev. Immunol. 2, 219-237
80. Suthanthiran, M., Anderson, M. E., Sharma, V. K., and Meis-ter, A. (1990). Glutathione regulates activation-dependent DNA synthesis in highly purified normal human T lymphocytes stimulated via the CD2 and CD3 antigens. Proc. Natl. Acad. Sci. U.S.A. 87, 3343-3347.
81. Szuster-Ciesielska, A., Hryciuk-Umer, E., Stepulak, A., Kupisz, K., and Kandefer-Szerszen, M. (2004). Reactive oxygen species production by blood neutrophils of patients with laryngeal carcinoma and antioxida-tive enzyme activity in their blood. Acta Oncol. 43, 252-258.
82. Tacke, F., and Kurts, C. (2011). Infiltrating monocytes versus resident Kupffer cells: do alternatively activated macrophages need to be targeted alternatively? Hepatology 54, 2267-2270.
83. Terabe, M., Matsui, S., Park, J. M., Mamura, M., Noben-Trauth, N., Donaldson, D. D., Chen, W., Wahl, S. M., Ledbetter, S., Pratt, B., Letterio, J. J., Paul, W. E., and Berzofsky, J. A. (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 immunosurveil-lance: abrogation prevents tumor recurrence. J. Exp. Med. 198, 1741- 1752.
84. Vickers, S. M., MacMillan-Crow, L. A., Green, M., Ellis, C., and Thompson, J. A. (1999). Association of increased immunostaining for inducible nitric oxide synthase and nitrotyrosine with fibroblast growth factor transformation in pancreatic cancer. Arch. Surg. 134, 245-251.
85. Wu, L., Yan, C., Czader, M., Foreman, O., Blum, J. S., Kapur, R., and Du, H.(2012). Inhibition of PPARgamma in myeloid-lineage cells induces systemic inflammation, immunosup-pression, and tumorigenesis. Blood 119, 115-126.
86. Yan, Z., Garg, S. K., and Banerjee, R. (2010). Regulatory T cells interfere with glutathione metabolism in dendritic cells and T cells. J. Biol. Chem. 285, 41525-41532.
87. Yan, Z., Garg, S. K., Kipnis, J., and Banerjee, R. (2009). Extracellular redox modulation by regulatory T cells. Nat. Chem. Biol. 5, 721-723.
88. Yang, R., Cai, Z., Zhang, Y., Yutzy, W. H. IV, Roby, K. F., and Roden, R. B. (2006). CD80 in immune suppression by mouse ovarian carcinoma-associated Gr-1+CD11b+ myeloid cells. Cancer Res. 66, 6807- 6815.
89. Youn, J. I., Nagaraj, S., Collazo, M., and Gabrilovich, D. I. (2008). Subsets of myeloid-derived suppressor cells in tumor-bearing mice. J. Immunol. 181, 5791-5802.
90. Young, M. R., Wright, M. A., Matthews, J. P., Malik, I., and Prechel, M. (1996). Suppression of T cell prolifer-ationby tumor-induced granulocyte-macrophage progenitor cells producing transforming growth factor-beta and nitric oxide. J. Immunol. 156, 1916-1922.
91. Zhang, W., Liang, S., Wu, J., and Horuzsko, A. (2008). Human inhibitory receptor immuno-globulin-like transcript 2 amplifies CD11b+Gr1+ myeloid-derived suppressor cells that promote long-term survival of allografts. Transplantation 86, 1125-1134.
92. Zhou, Z., French, D. L., Ma, G., Eisen-stein, S., Chen, Y., Divino, C. M., Keller, G., Chen, S. H., and Pan, P. Y. (2010). Development and function of myeloid-derived suppressor cells generated from mouse embryonic and hematopoietic stem cells. Stem Cells 28, 620-632.