Myeloid-Derived Suppressor Cells

  • Srinivas Nagaraj
  • Dmitry I. Gabrilovich
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 601)


The development of tumor-specific T cell tolerance is largely responsible for tumor escape. Accumulation of myeloid-derived suppressor cells (MDSCs) in animal tumor models as well as in cancer patients is involved in tumor-associated T cell tolerance. In recent years, it has become increasingly evident that MDSCs bring about antigen-specific T cell tolerance by various mechanisms, which is the focus of this chapter.


Myeloid Cell Arginase Activity Cell Tolerance Tumor Escape Immature Myeloid Cell 
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  1. Almand, B., Clark, J.I., Nikitina, E., 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 immunosuppression in cancer. J. Immunol. 166, 678–689.PubMedGoogle Scholar
  2. Almand, B., Resser, J., Lindman, B., Nadaf, S., Clark, J., Kwon, E., Carbone, D. and Gabrilovich, D. (2000) Clinical significance of defective dendritic cell differentiation in cancer. Clin. Cancer Res. 6, 1755–1766.PubMedGoogle Scholar
  3. Beck, C., Schreiber, K., Schreiber, H. and Rowley, D. (2001) 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, 19–28.CrossRefGoogle Scholar
  4. Boucher, J.L., Moali, C. and Tenu, J.P. (1999) Nitric oxyde biosynthesis, nitric oxide synthase inhibitors and arginase competition for L-arginine utilization. Cell. Mol. Life Sci. 55, 1015–1028.CrossRefPubMedGoogle Scholar
  5. Bronte, V., Apolloni, E., Cabrelle, A., Ronca, R., Serafini, P., Zamboni, P., Restifo, N. and Zanovello, P. (2000) Identification of a CD11b(+)/Gr-1(+)/CD31(+) myeloid progenitor capable of activating or suppressing CD8(+) T cells. Blood 96, 3838.PubMedGoogle Scholar
  6. Bronte, V., Casic, T., Gri, G., Gallana, K., Borsellino, G., Marrigo, I., Battistini, L., Iafrate, M., Prayer-Galletti, U., Pagano, F. and Viola, A. (2005) Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers. J. Exp. Med. 201, 1257–1268.CrossRefPubMedGoogle Scholar
  7. 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.PubMedGoogle Scholar
  8. Bronte, V., Serafini, P., Appoloni, E. and Zanovello, P. (2001) Tumor-induced immune dysfunctions caused by myeloid suppressor cells. J. Immunother. 24, 431–446.CrossRefPubMedGoogle Scholar
  9. Bronte, V., Serafini, P., De Santo, C., Marigo, I., Tosello, V., Mazzoni, A., Segal, D.M., Staib, C., Lowel, M., Sutter, G., Colombo, M.P. and Zanovello, P. (2003) IL-4-induced arginase 1 suppresses alloreactive T cells in tumor-bearing mice. J. Immunol. 170, 270–278.PubMedGoogle Scholar
  10. Bronte, V., Wang, M., Overwijk, W., Surman, D., 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.PubMedGoogle Scholar
  11. Cauley, L., Miller, E., Yen, M. and Swain, S. (2000) Superantigen-induced CD4 T cell tolerance mediated by myeloid cells and IFN-gamma. J. Immunol. 165, 6056.PubMedGoogle Scholar
  12. De Santo, C., Serafini, P., Marigo, I., Dolcetti, L., Bolla, M., Del Soldato, P., Melani, C., Guiducci, C., Colombo, M., Iezzi, M., Musiani, P., Zanovello, P. and Bronte, V. (2005) Nitroaspirin corrects immune dysfunction in tumor-bearing hosts and promotes tumor eradication by cancer vaccination. Proc. Natl. Acad. Sci. USA 102, 4185–4190.CrossRefPubMedGoogle Scholar
  13. Finke, J., Ferrone, S., Frey, A., Mufson, A. and Ochoa, A. (1999) Where have all the T cells gone? Mechanisms of immune evasion by tumors. Immunol. Today 20, 158–160.CrossRefPubMedGoogle Scholar
  14. Gabrilovich, D. (2004) Mechanisms and functional significance of tumour-induced dendritic-cell defects. Nat. Rev. Immunol. 4, 941–952.CrossRefPubMedGoogle Scholar
  15. Gabrilovich, D. and Pisarev, V. (2003) Tumor escape from immune response: mechanisms and targets of activity. Curr. Drug Targets 4, 525–536.CrossRefPubMedGoogle Scholar
  16. Gabrilovich, D.I., Velders, M., Sotomayor, E. and Kast, W.M. (2001) Mechanism of immune dysfunction in cancer mediated by immature Gr-1+ myeloid cells. J. Immunol. 166, 5398–5406.PubMedGoogle Scholar
  17. Hengesbach, L. and Hoag, K. (2004) Physiological concentrations of retinoic acid favor myeloid dendritic cell development over granulocyte development in cultures of bone marrow cells from mice. J. Nutr. 134, 2653–2659.PubMedGoogle Scholar
  18. Hestdal, K., Ruscetti, F., Ihle, J., Jacobsen, S., Dubois, C., Kopp, W., Longo, D. and Keller, J. (1991) Characterization and regulation of RB6-8C5 antigen expression on murine bone marrow cells. J. Immunol. 147, 22–28.PubMedGoogle Scholar
  19. Kusmartsev, S., Cheng, F., Yu, B., Nefedova, Y., Sotomayor, E., Lush, R. and Gabrilovich, D.I. (2003) All-trans-retinoic acid eliminates immature myeloid cells from tumor-bearing mice and improves the effect of vaccination. Cancer Res. 63, 4441–4449.PubMedGoogle Scholar
  20. Kusmartsev, S. and Gabrilovich, D.I. (2003) Inhibition of myeloid cell differentiation in cancer: the role of reactive oxygen species. J. Leukoc. Biol. 74, 186–196.CrossRefPubMedGoogle Scholar
  21. Kusmartsev, S. and Gabrilovich, D.I. (2005) STAT1 signaling regulates tumor-associated macrophage-mediated T cell deletion. J. Immunol. 174, 4880–4891.PubMedGoogle Scholar
  22. Kusmartsev, S., 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.PubMedGoogle Scholar
  23. 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.PubMedGoogle Scholar
  24. 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.PubMedGoogle Scholar
  25. Kuwata, T., Wang, I., Tamura, T., Ponnamperuma, R., Levine, R., Holmes, K., Morse, H., De Luca, L. and Ozato, K. (2000) Vitamin A deficiency in mice causes a systemic expansion of myeloid cells. Blood 95, 3349–3356.PubMedGoogle Scholar
  26. Lathers, D., Clark, J., Achille, N. and Young, M. (2004) Phase 1B study to improve immune responses in head and neck cancer patients using escalating doses of 25-hydroxyvitamin D3. Cancer Immunol. Immunother. 53, 422–430.CrossRefPubMedGoogle Scholar
  27. 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.CrossRefPubMedGoogle Scholar
  28. Liu, Y., Van Ginderachter, J., Brys, L., De Baetselier, P., Raes, G. and Geldhof, A. (2003) Nitric oxide-independent CTL suppression during tumor progression: association with arginase-producing (M2) myeloid cells. J. Immunol. 170, 5064–5074.PubMedGoogle Scholar
  29. 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.CrossRefPubMedGoogle Scholar
  30. Mencacci, A., Montagnoli, C., Bacci, A., Cenci, E., Pitzurra, L., Spreca, A., Kopf, M., Sharpe, A. and Romani, L. (2002) CD80+Gr-1+ myeloid cells inhibit development of antifungal Th1 immunity in mice with candidiasis. J. Immunol. 169, 3180–3190.PubMedGoogle Scholar
  31. Mirza, N., Fishman, M., Fricke, I., Dunn, M., Neuger, A.M., Frost, T.J., Lush, R.M., Antonia, S. and Gabrilovich, D.I. (2006) All-trans-retinoic acid improves differentiation of myeloid cells and immune response in cancer patients. Cancer Res. 66, 9299–9307.CrossRefPubMedGoogle Scholar
  32. Otsuji, M., Kimura, Y., Aoe, T., Okamoto, Y. and 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, 13119–13124.CrossRefPubMedGoogle Scholar
  33. Pandit, R., Lathers, D., Beal, N., Garrity, T. and Young, M. (2000) CD34+ immune suppressive cells in the peripheral blood of patients with head and neck cancer. Ann. Otol. Rhinol. Laryngol. 109, 749–754.PubMedGoogle Scholar
  34. Pelaez, B., Campillo, J., Lopez-Asenjo, J. and Subiza, J. (2001) Cyclophosphamide induces the development of early myeloid cells suppressing tumor growth by a nitric oxide-dependent mechanism. J. Immunol. 166, 6608.PubMedGoogle Scholar
  35. Rodriguez, P.C., Quiceno, D.G., Zabaleta, J., Ortiz, B., Zea, A.H., Piazuelo, M.B., Delgado, A., Correa, 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.CrossRefPubMedGoogle Scholar
  36. 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.CrossRefPubMedGoogle Scholar
  37. Rodriguez, P.C., Zea, A.H., DeSalvo, J., Culotta, K.S., Zabaleta, J., Quiceno, D.G., Ochoa, J.B. and Ochoa, A.C. (2003) L-Arginine consumption by macrophages modulates the expression of CD3 zeta chain in T lymphocytes. J. Immunol. 171, 1232–1239.PubMedGoogle Scholar
  38. Saio, M., Radoja, S., Marino, M. and Frey, A.B. (2001) Tumor-infiltrating macrophages induce apoptosis in activated CD8(+) T cells by a mechanism requiring cell contact and mediated by both the cell-associated form of TNF and nitric oxide. J. Immunol. 167, 5583–5593.PubMedGoogle Scholar
  39. Salvadori, S., Martinelli, G. and Zier, K. (2000) Resection of solid tumors reverses T cell defects and restores protective immunity. J. Immunol. 164, 2214.PubMedGoogle Scholar
  40. 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.PubMedGoogle Scholar
  41. Seung, L., Rowley, D., Dubeym, P. and Schreiber, H. (1995) Synergy between T cell immunity and inhibition of paracrine stimulation causes tumor rejection. Proc. Natl. Acad. Sci. USA 92, 6254–6258.CrossRefPubMedGoogle Scholar
  42. Sinha, P., Clements, V. and 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, 636–645.PubMedGoogle Scholar
  43. Subiza, J., Vinuela, J., Rodriguez, R. and De la Concha, E. (1989) Development of splenic natural suppressor (NS) cells in Ehrlich tumor-bearing mice. Int. J. Cancer 44, 307–314.CrossRefPubMedGoogle Scholar
  44. 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 immunosurveillance: abrogation prevents tumor recurrence. J. Exp. Med. 198, 1741–1752.CrossRefPubMedGoogle Scholar
  45. Walkley, C., Yuan, Y., Chandraratna, R. and McArthur, G. (2002) Retinoic acid receptor antagonism in vivo expands the numbers of precursor cells during granulopoiesis. Leukemia 16, 1763–1772.CrossRefPubMedGoogle Scholar
  46. Wells, A.D. (2003) Cell-cycle regulation of T cell responses—novel approaches to the control of alloimmunity. Immunol. Rev. 196, 25–36.CrossRefPubMedGoogle Scholar
  47. Wiers, K., Lathers, D., Wright, M. and Young, M. (2000) Vitamin D3 treatment to diminish the levels of immune suppressive CD34+ cells increases the effectiveness of adoptive immunotherapy. J. Immunother. 23, 115–124.CrossRefPubMedGoogle Scholar
  48. Wu, G. and Morris, S.M. (1998) Arginine metabolism: nitric oxide and beyond. Biochem. J. 336, 1–17.PubMedGoogle Scholar
  49. Yang, L., DeBusk, L., Fukuda, K., Fingleton, B., Green-Jarvis, B., Shyr, Y., Matrisian, L., Carbone, D. and Lin, P. (2004) Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell 6, 409–421.CrossRefPubMedGoogle Scholar
  50. Young, M. (2004) Tumor skewing of CD34+ progenitor cell differentiation into endothelial cells. Int. J. Cancer 109, 516–524.CrossRefPubMedGoogle Scholar
  51. Young, M., Ihm, J., Lozano, Y., Wright, M. and Prechel, M. (1995) Treating tumor-bearing mice with vitamin D3 diminishes tumor-induced myelopoiesis and associated immunosuppression, and reduces tumor metastasis and recurrence. Cancer Immunol. Immunother. 41, 37–45.PubMedGoogle Scholar
  52. Young, M.R. and Lathers, D.M. (1999) Myeloid progenitor cells mediate immune suppression in patients with head and neck cancers. Int. J. Immunopharmacol. 21, 241–252.CrossRefPubMedGoogle Scholar
  53. Young, M.R.I., Wright, M.A., Matthews, J.P., Malik, I. and Pandit, R. (1996) Suppression of T cell proliferation by tumor-induced granulocyte-macrophage progenitor cells producing transforming growth factor-β gnd nitric oxide. J. Immunol. 156, 1916–1921.PubMedGoogle Scholar
  54. Zea, A.H., Rodriguez, P.C., Atkins, M.B., Hernandez, C., Signoretti, S., Zabaleta, J., McDermott, D., Quiceno, D., Youmans, A., O’Neill, A., Mier, J. and Ochoa, A.C. (2005) Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: a mechanism of tumor evasion. Cancer Res. 65, 3044–3048.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.H. Lee Moffitt Cancer Center, University of South FloridaTampaUSA

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