Myeloid-Derived Suppressor Cells in Cancer: Mechanisms and Therapeutic Perspectives

Chapter

Abstract

Malignant cells create a chronic inflammatory microenvironment that facilitates their proliferation, promotes migration and invasion, and blunts any antitumor response by the innate and adaptive immune systems. This state of immunologic tolerance has been well characterized and is in part responsible for impairing the potential therapeutic benefits of immunotherapy approaches such as cancer vaccines and the adoptive transfer of T cells. One major mechanism by which tumor cells induce a chronic inflammatory microenvironment is through the recruitment of myeloid-derived suppressor cells (MDSC). MDSC are potent inhibitors of the immune response through the expression of arginase I which depletes l-arginine from the tumor microenvironment or by the production of various intermediates such as reactive nitrogen species and reactive oxygen species that can suppress T cell function. Here, we review recent concepts on how MDSC can regulate T cell function in cancer and other chronic inflammatory diseases and suggest possible therapeutic interventions to overcome this inhibitory effect.

Keywords

Tuberculosis Proline Interferon Arginine Tryptophan 

Notes

Acknowledgments

This work was supported by NIH/NCI grants 5R01CA082689, 5R01CA107974, and 5P20RR021970.

References

  1. 1.
    Miescher S, Whiteside TL, Carrel S, von Fliedner V (1986) Functional properties of tumor-infiltrating and blood lymphocytes in patients with solid tumors: effects of tumor cells and their supernatants on proliferative responses of lymphocytes. J Immunol 136:1899–1907PubMedGoogle Scholar
  2. 2.
    Miescher S, Stoeck M, Qiao L, Barras C, Barrelet L, von Fliedner V (1988) Preferential clonogenic deficit of CD8-positive T-lymphocytes infiltrating human solid tumors. Cancer Res 48:6992–6998PubMedGoogle Scholar
  3. 3.
    Whiteside TL, Miescher S, Moretta L, von Fliedner V (1988) Cloning and proliferating precursor frequencies of tumor-infiltrating lymphocytes from human solid tumors. Transplant Proc 20:342–343PubMedGoogle Scholar
  4. 4.
    Whiteside TL, Rabinowich H (1998) The role of Fas/FasL in immunosuppression induced by human tumors. Cancer Immunol Immunother 46:175–184CrossRefPubMedGoogle Scholar
  5. 5.
    Hellstrom I, Sjogren HO, Warner G, Hellstrom KE (1971) Blocking of cell-mediated tumor immunity by sera from patients with growing neoplasms. Int J Cancer 7:226–237CrossRefPubMedGoogle Scholar
  6. 6.
    Hellstrom KE, Hellstrom I, Nelson K (1983) Antigen-specific suppressor ("blocking") factors in tumor immunity. Biomembranes 11:365–388PubMedGoogle Scholar
  7. 7.
    Varesio L, Giovarelli M, Landolfo S, Forni G (1979) Suppression of proliferative response and lymphokine production during the progression of a spontaneous tumor. Cancer Res 39:4983–4988PubMedGoogle Scholar
  8. 8.
    Gattinoni L, Powell DJ Jr, Rosenberg SA, Restifo NP (2006) Adoptive immunotherapy for cancer: building on success. Nat Rev Immunol 6:383–393CrossRefPubMedGoogle Scholar
  9. 9.
    Stevenson FK (2005) Update on cancer vaccines. Curr Opin Oncol 17:573–577CrossRefPubMedGoogle Scholar
  10. 10.
    Dong H, Zhu G, Tamada K, Chen L (1999) B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med 5:1365–1369CrossRefPubMedGoogle Scholar
  11. 11.
    Klausner RD, Lippincott-Schwartz J, Bonifacino JS (1990) The T cell antigen receptor: insights into organelle biology. Annu Rev Cell Biol 6:403–431CrossRefPubMedGoogle Scholar
  12. 12.
    Kryczek I, Zou L, Rodriguez P, Zhu G, Wei S, Mottram P, Brumlik M, Cheng P, Curiel T, Myers L, Lackner A, Alvarez X, Ochoa A, Chen L, Zou W (2006) B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma. J Exp Med 203:871–881CrossRefPubMedGoogle Scholar
  13. 13.
    Kryczek I, Wei S, Zou L, Zhu G, Mottram P, Xu H, Chen L, Zou W (2006) Cutting edge: induction of B7-H4 on APCs through IL-10: novel suppressive mode for regulatory T cells. J Immunol 177:40–44PubMedGoogle Scholar
  14. 14.
    McHugh RS, Shevach EM, Margulies DH, Natarajan K (2001) A T cell receptor transgenic model of severe, spontaneous organ-specific autoimmunity. Eur J Immunol 31:2094–2103CrossRefPubMedGoogle Scholar
  15. 15.
    McHugh RS, Shevach EM (2002) Cutting edge: depletion of CD4+CD25+ regulatory T cells is necessary, but not sufficient, for induction of organ-specific autoimmune disease. J Immunol 168:5979–5983PubMedGoogle Scholar
  16. 16.
    Bronte V, Zanovello P (2005) Regulation of immune responses by L-arginineinine metabolism. Nat Rev Immunol 5:641–654CrossRefPubMedGoogle Scholar
  17. 17.
    Gabrilovich D (2004) Mechanisms and functional significance of tumour-induced dendritic-cell defects. Nat Rev Immunol 4:941–952CrossRefPubMedGoogle Scholar
  18. 18.
    Pekarek LA, Starr BA, Toledano AY, Schreiber H (1995) Inhibition of tumor growth by elimination of granulocytes. J Exp Med 181:435–440CrossRefPubMedGoogle Scholar
  19. 19.
    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 USA 92:6254–6258CrossRefPubMedGoogle Scholar
  20. 20.
    Young MR, Newby M, Wepsic HT (1987) Hematopoiesis and suppressor bone marrow cells in mice bearing large metastatic Lewis lung carcinoma tumors. Cancer Res 47:100–105PubMedGoogle Scholar
  21. 21.
    Zarour H, De SC, Lehmann F, Marchand M, Lethe B, Romero P, Boon T, Renauld JC (1996) The majority of autologous cytolytic T-lymphocyte clones derived from peripheral blood lymphocytes of a melanoma patient recognize an antigenic peptide derived from gene Pmel17/gp100. J Invest Dermatol 107:63–67CrossRefPubMedGoogle Scholar
  22. 22.
    Almand B, Clark JI, Nikitina E, van Beynen J, English NR, Knight SC, Carbone DP, Gabrilovich DI (2001) Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J Immunol 166:678–689PubMedGoogle Scholar
  23. 23.
    Almand B, Resser JR, Lindman B, Nadaf S, Clark JI, Kwon ED, Carbone DP, Gabrilovich DI (2000) Clinical significance of defective dendritic cell differentiation in cancer. Clin Cancer Res 6:1755–1766PubMedGoogle Scholar
  24. 24.
    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 67:425CrossRefPubMedGoogle Scholar
  25. 25.
    Gabrilovich DI, Nagaraj S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9:162–174CrossRefPubMedGoogle Scholar
  26. 26.
    Mellor AL, Munn DH (2004) IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol 4:762–774CrossRefPubMedGoogle Scholar
  27. 27.
    Munn DH, Sharma MD, Baban B, Harding HP, Zhang Y, Ron D, Mellor AL (2005) GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity 22:633–642CrossRefPubMedGoogle Scholar
  28. 28.
    Mizoguchi H, O'Shea JJ, Longo DL, Loeffler CM, McVicar DW, Ochoa AC (1992) Alterations in signal transduction molecules in T lymphocytes from tumor-bearing mice. Science 258:1795–1798CrossRefPubMedGoogle Scholar
  29. 29.
    Ghosh P, Sica A, Young HA, Ye J, Franco JL, Wiltrout RH, Longo DL, Rice NR, Komschlies KL (1994) Alterations in NF kappa B/Rel family proteins in splenic T-cells from tumor-bearing mice and reversal following therapy. Cancer Res 54:2969–2972PubMedGoogle Scholar
  30. 30.
    Li X, Liu J, Park JK, Hamilton TA, Rayman P, Klein E, Edinger M, Tubbs R, Bukowski R, Finke J (1994) T cells from renal cell carcinoma patients exhibit an abnormal pattern of kappa B-specific DNA-binding activity: a preliminary report. Cancer Res 54:5424–5429PubMedGoogle Scholar
  31. 31.
    Finke JH, Zea AH, Stanley J, Longo DL, Mizoguchi H, Tubbs RR, Wiltrout RH, O'Shea JJ, Kudoh S, Klein E, Ochoa AC (1993) Loss of T-cell receptor zeta chain and p56 lck in T-cells infiltrating human renal cell carcinoma. Cancer Res 53:5613–5616PubMedGoogle Scholar
  32. 32.
    Kono K, Ressing ME, Brandt RM, Melief CJ, Potkul RK, Andersson B, Petersson M, Kast WM, Kiessling R (1996) Decreased expression of signal-transducing zeta chain in peripheral T cells and natural killer cells in patients with cervical cancer. Clin Cancer Res 2:1825–1828PubMedGoogle Scholar
  33. 33.
    Zea AH, Curti BD, Longo DL, Alvord WG, Strobl SL, Mizoguchi H, Creekmore SP, O'Shea JJ, Powers GC, Urba WJ et al (1995) Alterations in T cell receptor and signal transduction molecules in melanoma patients. Clin Cancer Res 1:1327–1335PubMedGoogle Scholar
  34. 34.
    Kuss I, Saito T, Johnson JT, Whiteside TL (1999) Clinical significance of decreased zeta chain expression in peripheral blood lymphocytes of patients with head and neck cancer. Clin Cancer Res 5:329–334PubMedGoogle Scholar
  35. 35.
    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 USA 93:13119–13124CrossRefPubMedGoogle Scholar
  36. 36.
    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 26:1308–1313CrossRefPubMedGoogle Scholar
  37. 37.
    Corsi MM, Maes HH, Wasserman K, Fulgenzi A, Gaja G, Ferrero ME (1998) Protection by L-2-oxothiazolidine-4-carboxylic acid of hydrogen peroxide-induced CD3zeta and CD16zeta chain down-regulation in human peripheral blood lymphocytes and lymphokine-activated killer cells. Biochem Pharmacol 56:657–662CrossRefPubMedGoogle Scholar
  38. 38.
    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 61:4756–4760PubMedGoogle Scholar
  39. 39.
    Rabinowich H, Reichert TE, Kashii Y, Gastman BR, Bell MC, Whiteside TL (1998) Lymphocyte apoptosis induced by Fas li. J Clin Invest 101:2579–2588CrossRefPubMedGoogle Scholar
  40. 40.
    Uzzo RG, Rayman P, Kolenko V, Clark PE, Bloom T, Ward AM, Molto L, Tannenbaum C, Worford LJ, Bukowski R, Tubbs R, Hsi ED, Bander NH, Novick AC, Finke JH (1999) Mechanisms of apoptosis in T cells from patients with renal cell carcinoma. Clin Cancer Res 5:1219–1229PubMedGoogle Scholar
  41. 41.
    Baniyash M (2004) TCR zeta-chain downregulation: curtailing an excessive inflammatory immune response. Nat Rev Immunol 4:675–687CrossRefPubMedGoogle Scholar
  42. 42.
    Bronstein-Sitton N, Cohen-Daniel L, Vaknin I, Ezernitchi AV, Leshem B, Halabi A, Houri-Hadad Y, Greenbaum E, Zakay-Rones Z, Shapira L, Baniyash M (2003) Sustained exposure to bacterial antigen induces interferon-gamma-dependent T cell receptor zeta down-regulation and impaired T cell function. Nat Immunol 4:957–964CrossRefPubMedGoogle Scholar
  43. 43.
    Meyer C, Sevko A, Ramacher M, Bazhin AV, Falk CS, Osen W, Borrello I, Kato M, Schadendorf D, Baniyash M, Umansky V (2011) Chronic inflammation promotes myeloid-derived suppressor cell activation blocking antitumor immunity in transgenic mouse melanoma model. Proc Natl Acad Sci USA 108:17111–17116CrossRefPubMedGoogle Scholar
  44. 44.
    Zea AH, Culotta KS, Ali J, Mason C, Park HJ, Zabaleta J, Garcia LF, Ochoa AC (2006) Decreased expression of CD3zeta and nuclear transcription factor kappa B in patients with pulmonary tuberculosis: potential mechanisms and reversibility with treatment. J Infect Dis 194:1385–1393CrossRefPubMedGoogle Scholar
  45. 45.
    Zea AH, Ochoa MT, Ghosh P, Longo DL, Alvord WG, Valderrama L, Falabella R, Harvey LK, Saravia N, Moreno LH, Ochoa AC (1998) Changes in expression of signal transduction proteins in T lymphocytes of patients with leprosy. Infect Immun 66:499–504PubMedGoogle Scholar
  46. 46.
    Makarenkova VP, Bansal V, Matta BM, Perez LA, Ochoa JB (2006) CD11b+/Gr-1+ myeloid suppressor cells cause T cell dysfunction after traumatic stress. J Immunol 176:2085–2094PubMedGoogle Scholar
  47. 47.
    Kirk SJ, Regan MC, Wasserkrug HL, Sodeyama M, Barbul A (1992) Arginine enhances T-cell responses in athymic nude mice. JPEN J Parenter Enteral Nutr 16:429–432CrossRefPubMedGoogle Scholar
  48. 48.
    Ochoa JB, Bernard AC, Mistry SK, Morris SM Jr, Figert PL, Maley ME, Tsuei BJ, Boulanger BR, Kearney PA (2000) Trauma increases extrahepatic arginase activity. Surgery 127:419–426CrossRefPubMedGoogle Scholar
  49. 49.
    Ochoa JB, Strange J, Kearney P, Gellin G, Endean E, Fitzpatrick E (2001) Effects of L-arginineinine on the proliferation of T lymphocyte subpopulations. JPEN J Parenter Enteral Nutr 25:23–29CrossRefPubMedGoogle Scholar
  50. 50.
    Barbul A, Rettura G, Levenson SM, Seifter E (1977) Arginine: a thymotropic and wound-healing promoting agent. Surg Forum 28:101–103PubMedGoogle Scholar
  51. 51.
    Albina JE, Caldwell MD, Henry WL Jr, Mills CD (1989) Regulation of macrophage functions by L-arginineinine. J Exp Med 169:1021–1029CrossRefPubMedGoogle Scholar
  52. 52.
    Rodriguez PC, Zea AH, Culotta KS, Zabaleta J, Ochoa JB, Ochoa AC (2002) Regulation of T cell receptor CD3 zeta chain expression by L-arginineinine. J Biol Chem 277:21123–21129CrossRefPubMedGoogle Scholar
  53. 53.
    Taheri F, Ochoa JB, Faghiri Z, Culotta K, Park HJ, Lan MS, Zea AH, Ochoa AC (2001) L-arginineinine regulates the expression of the T-cell receptor zeta chain (CD3zeta) in Jurkat cells. Clin Cancer Res 7:958s–965sPubMedGoogle Scholar
  54. 54.
    Zea AH, Rodriguez PC, Culotta KS, Hernandez CP, DeSalvo J, Ochoa JB, Park HJ, Zabaleta J, Ochoa AC (2004) L-arginineinine modulates CD3zeta expression and T cell function in activated human T lymphocytes. Cell Immunol 232:21–31CrossRefPubMedGoogle Scholar
  55. 55.
    Brosnan ME, Brosnan JT (2004) Renal arginine metabolism. J Nutr 134:2791S–2795SPubMedGoogle Scholar
  56. 56.
    Nieves C Jr, Langkamp-Henken B (2002) Arginine and immunity: a unique perspective. Biomed Pharmacother 56:471–482CrossRefPubMedGoogle Scholar
  57. 57.
    Closs EI, Simon A, Vekony N, Rotmann A (2004) Plasma membrane transporters for arginine. J Nutr 134:2752S–2759SPubMedGoogle Scholar
  58. 58.
    Amber IJ, Hibbs JB Jr, Parker CJ, Johnson BB, Taintor RR, Vavrin Z (1991) Activated macrophage conditioned medium: identification of the soluble factors inducing cytotoxicity and the L-arginineinine dependent effector mechanism. J Leukoc Biol 49:610–620PubMedGoogle Scholar
  59. 59.
    Hibbs JB Jr, Taintor RR, Vavrin Z (1987) Macrophage cytotoxicity: role for L-arginineinine deiminase and imino nitrogen oxidation to nitrite. Science 235:473–476CrossRefPubMedGoogle Scholar
  60. 60.
    Morris SM Jr (2002) Regulation of enzymes of the urea cycle and arginine metabolism. Annu Rev Nutr 22:87–105CrossRefPubMedGoogle Scholar
  61. 61.
    Iyo AH, Zhu MY, Ordway GA, Regunathan S (2006) Expression of arginine decarboxylase in brain regions and neuronal cells. J Neurochem 96:1042–1050CrossRefPubMedGoogle Scholar
  62. 62.
    Zhu MY, Iyo A, Piletz JE, Regunathan S (2004) Expression of human arginine decarboxylase, the biosynthetic enzyme for agmatine. Biochim Biophys Acta 1670:156–164CrossRefPubMedGoogle Scholar
  63. 63.
    Cullen ME, Yuen AH, Felkin LE, Smolenski RT, Hall JL, Grindle S, Miller LW, Birks EJ, Yacoub MH, Barton PJ (2006) Myocardial expression of the arginine:glycine amidinotransferase gene is elevated in heart failure and normalized after recovery: potential implications for local creatine synthesis. Circulation 114:I16–I20CrossRefPubMedGoogle Scholar
  64. 64.
    Item CB, Stockler-Ipsiroglu S, Stromberger C, Muhl A, Alessandri MG, Bianchi MC, Tosetti M, Fornai F, Cioni G (2001) Arginine:glycine amidinotransferase deficiency: the third inborn error of creatine metabolism in humans. Am J Hum Genet 69:1127–1133CrossRefPubMedGoogle Scholar
  65. 65.
    Hesse M, Modolell M, La Flamme AC, Schito M, Fuentes JM, Cheever AW, Pearce EJ, Wynn TA (2001) Differential regulation of nitric oxide synthase-2 and arginase-1 by type 1/type 2 cytokines in vivo: granulomatous pathology is shaped by the pattern of L-arginineinine metabolism. J Immunol 167:6533–6544PubMedGoogle Scholar
  66. 66.
    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 163:3771–3777PubMedGoogle Scholar
  67. 67.
    Munder M, Eichmann K, Modolell M (1998) Alternative metabolic states in murine macrophages reflected by the nitric oxide synthase/arginase balance: competitive regulation by CD4+ T cells correlates with Th1/Th2 phenotype. J Immunol 160:5347–5354PubMedGoogle Scholar
  68. 68.
    Rutschman R, Lang R, Hesse M, Ihle JN, Wynn TA, Murray PJ (2001) Cutting edge: Stat6-dependent substrate depletion regulates nitric oxide production. J Immunol 166:2173–2177PubMedGoogle Scholar
  69. 69.
    Rodriguez PC, Zea AH, DeSalvo J, Culotta KS, Zabaleta J, Quiceno DG, Ochoa JB, Ochoa AC (2003) L-arginineinine consumption by macrophages modulates the expression of CD3zeta chain in T lymphocytes. J Immunol 171:1232–1239PubMedGoogle Scholar
  70. 70.
    Chicoine LG, Paffett ML, Young TL, Nelin LD (2004) Arginase inhibition increases nitric oxide production in bovine pulmonary arterial endothelial cells. Am J Physiol Lung Cell Mol Physiol 287:L60–L68CrossRefPubMedGoogle Scholar
  71. 71.
    Zhang C, Hein TW, Wang W, Miller MW, Fossum TW, McDonald MM, Humphrey JD, Kuo L (2004) Upregulation of vascular arginase in hypertension decreases nitric oxide-mediated dilation of coronary arterioles. Hypertension 44:935–943CrossRefPubMedGoogle Scholar
  72. 72.
    Lee J, Ryu H, Ferrante RJ, Morris SM Jr, Ratan RR (2003) Translational control of inducible nitric oxide synthase expression by arginine can explain the arginine paradox. Proc Natl Acad Sci USA 100:4843–4848CrossRefPubMedGoogle Scholar
  73. 73.
    Santhanam L, Lim HK, Lim HK, Miriel V, Brown T, Patel M, Balanson S, Ryoo S, Anderson M, Irani K, Khanday F, Di CL, 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 101:692–702CrossRefPubMedGoogle Scholar
  74. 74.
    Deignan JL, Livesay JC, Yoo PK, Goodman SI, O'Brien WE, Iyer RK, Cederbaum SD, Grody WW (2006) Ornithine deficiency in the arginase double knockout mouse. Mol Genet Metab 89:87–96CrossRefPubMedGoogle Scholar
  75. 75.
    Iyer RK, Yoo PK, Kern RM, Rozengurt N, Tsoa R, O'Brien WE, Yu H, Grody WW, Cederbaum SD (2002) Mouse model for human arginase deficiency. Mol Cell Biol 22:4491–4498CrossRefPubMedGoogle Scholar
  76. 76.
    Bronte V, Serafini P, De Santo C, Marigo I, Tosello V, Mazzoni A, Segal DM, Staib C, Lowel M, Sutter G, Colombo MP, Zanovello P (2003) IL-4-induced arginase 1 suppresses alloreactive T cells in tumor-bearing mice. J Immunol 170:270–278PubMedGoogle Scholar
  77. 77.
    Kusmartsev S, Gabrilovich DI (2005) STAT1 signaling regulates tumor-associated macrophage-mediated T cell deletion. J Immunol 174:4880–4891PubMedGoogle Scholar
  78. 78.
    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 13:828–835CrossRefPubMedGoogle Scholar
  79. 79.
    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 64:5839–5849CrossRefPubMedGoogle Scholar
  80. 80.
    Sinha P, Clements VK, Ostrand-Rosenberg S (2005) Interleukin-13-regulated M2 macrophages in combination with myeloid suppressor cells block immune surveillance against metastasis. Cancer Res 65:11743–11751CrossRefPubMedGoogle Scholar
  81. 81.
    Van Ginderachter JA, Meerschaut S, Liu Y, Brys L, De Groeve K, Hassanzadeh Ghassabeh G, Raes G, De Baetselier P (2006) Peroxisome proliferator-activated receptor gamma (PPARgamma) ligands reverse CTL suppression by alternatively activated (M2) macrophages in cancer. Blood 108:525–535CrossRefPubMedGoogle Scholar
  82. 82.
    Gabrilovich DI, Velders MP, Sotomayor EM, Kast WM (2001) Mechanism of immune dysfunction in cancer mediated by immature Gr-1+ myeloid cells. J Immunol 166:5398–5406PubMedGoogle Scholar
  83. 83.
    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 172:989–999PubMedGoogle Scholar
  84. 84.
    Gallina G, Dolcetti L, Serafini P, De SC, Marigo I, Colombo MP, Basso G, Brombacher F, Borrello I, Zanovello P, Bicciato S, Bronte V (2006) Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells. J Clin Invest 116:2777–2790CrossRefPubMedGoogle Scholar
  85. 85.
    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 174:636–645PubMedGoogle Scholar
  86. 86.
    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 66:1123–1131CrossRefPubMedGoogle Scholar
  87. 87.
    Pan PY, Wang GX, Yin B, Ozao J, Ku T, Divino CM, Chen SH (2008) Reversion of immune tolerance in advanced malignancy: modulation of myeloid derived suppressor cell development by blockade of SCF function. Blood 111:219–228CrossRefPubMedGoogle Scholar
  88. 88.
    Rodriguez PC, Quiceno DG, Ochoa AC (2007) L-arginineinine availability regulates T-lymphocyte cell-cycle progression. Blood 109:1568–1573CrossRefPubMedGoogle Scholar
  89. 89.
    Kato JY (1997) Control of G1 progression by D-type cyclins: key event for cell proliferation. Leukemia 11(suppl 3):347–351PubMedGoogle Scholar
  90. 90.
    Rodriguez PC, Hernandez CP, Morrow K, Sierra R, Zabaleta J, Wyczechowska DD, Ochoa AC (2010) L-arginineinine deprivation regulates cyclin D3 mRNA stability in human T cells by controlling HuR expression. J Immunol 185:5198–5204CrossRefPubMedGoogle Scholar
  91. 91.
    Chang CI, Liao JC, Kuo L (2001) Macrophage arginase promotes tumor cell growth and suppresses nitric oxide-mediated tumor cytotoxicity. Cancer Res 61:1100–1106PubMedGoogle Scholar
  92. 92.
    Singh R, Pervin S, Karimi A, Cederbaum S, Chaudhuri G (2000) Arginase activity in human breast cancer cell lines: N(omega)-hydroxy-L- arginine selectively inhibits cell proliferation and induces apoptosis in MDA-MB-468 cells. Cancer Res 60:3305–3312PubMedGoogle Scholar
  93. 93.
    Suer GS, Yoruk Y, Cakir E, Yorulmaz F, Gulen S (1999) Arginase and ornithine, as markers in human non-small cell lung carcinoma. Cancer Biochem Biophys 17:125–131Google Scholar
  94. 94.
    Youn JI, Nagaraj S, Collazo M, Gabrilovich DI (2008) Subsets of myeloid-derived suppressor cells in tumor-bearing mice. J Immunol 181:5791–5802PubMedGoogle Scholar
  95. 95.
    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 96:3838–3846PubMedGoogle Scholar
  96. 96.
    Holda JH, Maier T, Claman HN (1985) Murine graft-versus-host disease across minor barriers: immunosuppressive aspects of natural suppressor cells. Immunol Rev 88:87–105CrossRefPubMedGoogle Scholar
  97. 97.
    Sica A, Bronte V (2007) Altered macrophage differentiation and immune dysfunction in tumor development. J Clin Invest 117:1155–1166CrossRefPubMedGoogle Scholar
  98. 98.
    Solito S, Falisi E, Diaz-Montero CM, Doni A, Pinton L, Rosato A, Francescato S, Basso G, Zanovello P, Onicescu G, Garrett-Mayer E, Montero AJ, Bronte V, Mandruzzato S (2011) A human promyelocytic-like population is responsible for the immune suppression mediated by myeloid-derived suppressor cells. Blood 118:2254–2265CrossRefPubMedGoogle Scholar
  99. 99.
    Rodriguez PC, Ernstoff MS, Hernandez C, Atkins M, Zabaleta J, Sierra R, Ochoa AC (2009) Arginase I-producing myeloid-derived suppressor cells in renal cell carcinoma are a subpopulation of activated granulocytes. Cancer Res 69:1553–1560CrossRefPubMedGoogle Scholar
  100. 100.
    Greten TF, Manns MP, Korangy F (2011) Myeloid derived suppressor cells in human diseases. Int Immunopharmacol 11:802–807CrossRefPubMedGoogle Scholar
  101. 101.
    Zea AH, Rodriguez PC, Atkins MB, Hernandez C, Signoretti S, Zabaleta J, McDermott D, Quiceno D, Youmans A, O'Neill A, Mier J, Ochoa AC (2005) Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: a mechanism of tumor evasion. Cancer Res 65:3044–3048PubMedGoogle Scholar
  102. 102.
    Rodgers S, Rees RC, Hancock BW (1994) Changes in the phenotypic characteristics of eosinophils from patients receiving recombinant human interleukin-2 (rhIL-2) therapy. Br J Haematol 86:746–753CrossRefPubMedGoogle Scholar
  103. 103.
    Munder M, Mollinedo F, Calafat J, Canchado J, Gil-Lamaignere C, Fuentes JM, Luckner C, Doschko G, Soler G, Eichmann K, Muller FM, Ho AD, Goerner M, Modolell M (2005) Arginase I is constitutively expressed in human granulocytes and participates in fungicidal activity. Blood 105:2549–2556CrossRefPubMedGoogle Scholar
  104. 104.
    Jacobsen LC, Theilgaard-Monch K, Christensen EI, Borregaard N (2007) Arginase 1 is expressed in myelocytes/metamyelocytes and localized in gelatinase granules of human neutrophils. Blood 109:3084–3087PubMedGoogle Scholar
  105. 105.
    Kropf P, Baud D, Marshall SE, Munder M, Mosley A, Fuentes JM, Bangham CR, Taylor GP, Herath S, Choi BS, Soler G, Teoh T, Modolell M, Muller I (2007) Arginase activity mediates reversible T cell hyporesponsiveness in human pregnancy. Eur J Immunol 37:935–945CrossRefPubMedGoogle Scholar
  106. 106.
    Munder M, Schneider H, Luckner C, Giese T, Langhans CD, Fuentes JM, Kropf P, Mueller I, Kolb A, Modolell M, Ho AD (2006) Suppression of T-cell functions by human granulocyte arginase. Blood 108:1627–1634CrossRefPubMedGoogle Scholar
  107. 107.
    Dolcetti L, Peranzoni E, Ugel S, Marigo I, Fernandez Gomez A, Mesa C, Geilich M, Winkels G, Traggiai E, Casati A, Grassi F, Bronte V (2010) Hierarchy of immunosuppressive strength among myeloid-derived suppressor cell subsets is determined by GM-CSF. Eur J Immunol 40:22–35CrossRefPubMedGoogle Scholar
  108. 108.
    Ohm JE, Carbone DP (2001) VEGF as a mediator of tumor-associated immunodeficiency. Immunol Res 23:263–272CrossRefPubMedGoogle Scholar
  109. 109.
    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 92:4150–4166PubMedGoogle Scholar
  110. 110.
    Oyama T, Ran S, Ishida T, Nadaf S, Kerr L, Carbone DP, Gabrilovich DI (1998) Vascular endothelial growth factor affects dendritic cell maturation through the inhibition of nuclear factor-kappa B activation in hemopoietic progenitor cells. J Immunol 160:1224–1232PubMedGoogle Scholar
  111. 111.
    Kusmartsev S, Cheng F, Yu B, Nefedova Y, Sotomayor E, Lush R, Gabrilovich D (2003) All-trans-retinoic acid eliminates immature myeloid cells from tumor-bearing mice and improves the effect of vaccination. Cancer Res 63:4441–4449PubMedGoogle Scholar
  112. 112.
    Solheim JC, Reber AJ, Ashour AE, Robinson S, Futakuchi M, Kurz SG, Hood K, Fields RR, Shafer LR, Cornell D, Sutjipto S, Zurawski S, LaFace DM, Singh RK, Talmadge JE (2007) Spleen but not tumor infiltration by dendritic and T cells is increased by intravenous adenovirus-Flt3 ligand injection. Cancer Gene Ther 14:364–371CrossRefPubMedGoogle Scholar
  113. 113.
    Cheng P, Corzo CA, Luetteke N, Yu B, Nagaraj S, Bui MM, Ortiz M, Nacken W, Sorg C, Vogl T, Roth J, Gabrilovich DI (2008) Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein. J Exp Med 205:2235–2249CrossRefPubMedGoogle Scholar
  114. 114.
    Ko JS, Rayman P, Ireland J, Swaidani S, Li G, Bunting KD, Rini B, Finke JH, Cohen PA (2010) Direct and differential suppression of myeloid-derived suppressor cell subsets by sunitinib is compartmentally constrained. Cancer Res 70:3526–3536CrossRefPubMedGoogle Scholar
  115. 115.
    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 14:8270–8278CrossRefPubMedGoogle Scholar
  116. 116.
    Le HK, Graham L, Cha E, Morales JK, Manjili MH, Bear HD (2009) Gemcitabine directly inhibits myeloid derived suppressor cells in BALB/c mice bearing 4T1 mammary carcinoma and augments expansion of T cells from tumor-bearing mice. Int Immunopharmacol 9:900–909CrossRefPubMedGoogle Scholar
  117. 117.
    Mundy-Bosse BL, Lesinski GB, Jaime-Ramirez AC, Benninger K, Khan M, Kuppusamy P, Guenterberg K, Kondadasula SV, Chaudhury AR, La Perle KM, Kreiner M, Young G, Guttridge DC, Carson WE III (2011) Myeloid-derived suppressor cell inhibition of the IFN response in tumor-bearing mice. Cancer Res 71:5101–5110CrossRefPubMedGoogle Scholar
  118. 118.
    Toh B, Wang X, Keeble J, Sim WJ, Khoo K, Wong WC, Kato M, Prevost-Blondel A, Thiery JP, Abastado JP (2011) Mesenchymal transition and dissemination of cancer cells is driven by myeloid-derived suppressor cells infiltrating the primary tumor. PLoS Biol 9:e1001162CrossRefPubMedGoogle Scholar
  119. 119.
    Vincent J, Mignot G, Chalmin F, Ladoire S, Bruchard M, Chevriaux A, Martin F, Apetoh L, Rebe C, Ghiringhelli F (2010) 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res 70:3052–3061CrossRefPubMedGoogle Scholar
  120. 120.
    Rodriguez PC, Hernandez CP, Quiceno D, Dubinett SM, Zabaleta J, Ochoa JB, Gilbert J, Ochoa AC (2005) Arginase I in myeloid suppressor cells is induced by COX-2 in lung carcinoma. J Exp Med 202:931–939CrossRefPubMedGoogle Scholar
  121. 121.
    Sinha P, Clements VK, Fulton AM, Ostrand-Rosenberg S (2007) Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells. Cancer Res 67:4507–4513CrossRefPubMedGoogle Scholar
  122. 122.
    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 7:140–151CrossRefPubMedGoogle Scholar
  123. 123.
    Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3:721–732CrossRefPubMedGoogle Scholar
  124. 124.
    Rotondo R, Barisione G, Mastracci L, Grossi F, Orengo AM, Costa R, Truini M, Fabbi M, Ferrini S, Barbieri O (2009) IL-8 induces exocytosis of arginase 1 by neutrophil polymorphonuclears in nonsmall cell lung cancer. Int J Cancer 125:887–893CrossRefPubMedGoogle Scholar
  125. 125.
    El Kasmi KC, Qualls JE, Pesce JT, Smith AM, Thompson RW, Henao-Tamayo M, Basaraba RJ, Konig T, Schleicher U, Koo MS, Kaplan G, Fitzgerald KA, Tuomanen EI, Orme IM, Kanneganti TD, Bogdan C, Wynn TA, Murray PJ (2008) Toll-like receptor-induced arginase 1 in macrophages thwarts effective immunity against intracellular pathogens. Nat Immunol 9:1399–1406CrossRefPubMedGoogle Scholar
  126. 126.
    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 USA 102:4185–4190CrossRefPubMedGoogle Scholar
  127. 127.
    Serafini P, Meckel K, Kelso M, Noonan K, Califano J, Koch W, Dolcetti L, Bronte V, Borrello I (2006) Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J Exp Med 203:2691–2702CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of Microbiology, Immunology and ParasitologyLouisiana State University Health Sciences CenterNew OrleansUSA
  2. 2.Stanley S. Scott Cancer CenterLouisiana State University Health Sciences CenterNew OrleansUSA
  3. 3.Department of PediatricsLouisiana State University Health Sciences CenterNew OrleansUSA

Personalised recommendations