Gangliosides as Immunomodulators

  • Miroslava Potapenko
  • Galina V. Shurin
  • Joel de León
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 601)


Gangliosides are glycosphingolipids expressed at the outer leaflet of the plasmatic membrane of cells from vertebrate organisms. These molecules exert diverse biological functions including modulation of the immune system responses. Aberrant expression of gangliosides has been demonstrated on malignant cells. Besides expression on tumor cell membranes, gangliosides are also shed in the tumor microenvironment and eventually circulate in patients blood. Gangliosides derived from tumors posses the capability to affect the immune system responses by altering the function of lymphocytes and antigen-presenting cells and promoting tumor growth. These molecules can be considered as tumor weapons directed to attack and destroy immunosurveillance mechanisms devoted to control cancer progression.


Sialic Acid Neuraminic Acid Immune System Response GD1a Ganglioside Ganglioside Biosynthesis 
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  1. Angata, T. and Varki, A. (2002) Chemical diversity in the sialic acids and related alpha-keto acids: an evolutionary perspective. Chem. Rev. 102, 439–469.CrossRefPubMedGoogle Scholar
  2. Bennaceur, K., Popa, I., Portoukalian, J., Berthier-Vergnes, O. and Peguet-Navarro, J. (2006) Melanoma-derived gangliosides impair migratory and antigen-presenting function of human epidermal Langerhans cells and induce their apoptosis. Int. Immunol. 18, 879–886.CrossRefPubMedGoogle Scholar
  3. Bergelson, L.D. (1995) Serum gangliosides as endogenous immunomodulators. Immunol. Today 16, 483–486.Google Scholar
  4. Boon, T., Coulie, P.G. and Van den Eynde, B. (1997) Tumor antigens recognized by T cells. Immunol. Today 18, 267–268.Google Scholar
  5. Bronnum, H., Seested, T., Hellgren, L.I., Brix, S. and Frokiaer, H. (2005) Milk-derived GM(3) and GD(3) differentially inhibit dendritic cell maturation and effector functionalities. Scand. J. Immunol. 61, 551–557.CrossRefPubMedGoogle Scholar
  6. Caldwell, S., Heitger, A., Shen, W., Liu, Y., Taylor, B. and Ladisch, S. (2003) Mechanisms of ganglioside inhibition of APC function. J. Immunol. 171, 1676–1683.PubMedGoogle Scholar
  7. Cheresh, D.A., Pierschbacher, M.D., Herzig, M.A. and Mujoo, K. (1986) Disialogangliosides GD2 and GD3 are involved in the attachment of human melanoma and neuroblastoma cells to extracellular matrix proteins. J. Cell Biol. 102, 688–696.CrossRefPubMedGoogle Scholar
  8. Colell, A., Garcia-Ruiz, C., Roman, J., Ballesta, A. and Fernandez-Checa, J.C. (2001) Ganglioside GD3 enhances apoptosis by suppressing the nuclear factor-kappa B-dependent survival pathway. FASEB J. 15, 1068–1070.PubMedGoogle Scholar
  9. Crespo, F.A., Sun, X., Cripps, J.G. and Fernandez-Botran, R. (2006) The immunoregulatory effects of gangliosides involve immune deviation favoring type-2 T cell responses. J. Leukoc. Biol. 79, 586–595.CrossRefPubMedGoogle Scholar
  10. de Leon, J., Fernandez, A., Mesa, C., Clavel, M. and Fernandez, L.E. (2006) Role of tumour-associated N-glycolylated variant of GM3 ganglioside in cancer progression: effect over CD4 expression on T cells. Cancer Immunol. Immunother. 55, 443–450.CrossRefPubMedGoogle Scholar
  11. De Maria, R., Lenti, L., Malisan, F., d’Agostino, F., Tomassini, B., Zeuner, A., Rippo, M.R. and Testi, R. (1997) Requirement for GD3 ganglioside in CD95- and ceramide-induced apoptosis. Science 277, 1652–1655.CrossRefPubMedGoogle Scholar
  12. Deng, W., Li, R. and Ladisch, S. (2000) Influence of cellular ganglioside depletion on tumor formation. J. Natl. Cancer Inst. 92, 912–917.CrossRefPubMedGoogle Scholar
  13. Diatlovitskaia, E.V., Kliuchareva, E.V., Matveeva, V.A., Sinitsyna, E.V. and Akhmed-Zade, A.S. (1985) Effect of gangliosides on the cytotoxic activity of natural killers from Syrian hamsters. Biochemistry (Russia) 50, 1514–1516.Google Scholar
  14. Feizi, T. (1985) Demonstration by monoclonal antibodies that carbohydrate structures of glycoproteins and glycolipids are onco-developmental antigens. Nature 314, 53–57.CrossRefPubMedGoogle Scholar
  15. Finke, J.H., Rayman, P., George, R., Tannenbaum, C.S., Kolenko, V., Uzzo, R., Novick, A.C. and Bukowski, R.M. (2001) Tumor-induced sensitivity to apoptosis in T cells from patients with renal cell carcinoma: role of nuclear factor-kappaB suppression. Clin. Cancer Res. 7, 940s–946s.PubMedGoogle Scholar
  16. Fujitani, M., Kawai, H., Proia, R.L., Kashiwagi, A., Yasuda, H. and Yamashita, T. (2005) Binding of soluble myelin-associated glycoprotein to specific gangliosides induces the association of p75NTR to lipid rafts and signal transduction. J. Neurochem. 94, 15–21.CrossRefPubMedGoogle Scholar
  17. Gonwa, T.A., Westrick, M.A. and Macher, B.A. (1984) Inhibition of mitogen- and antigen-induced lymphocyte activation by human leukemia cell gangliosides. Cancer Res. 44, 3467–3470.PubMedGoogle Scholar
  18. Gottschalk, A. (1955) Structural relation between sialic acid, neuraminic acid, and 2-carboxypyrrole. Nature 176, 881–882.CrossRefGoogle Scholar
  19. Hakomori, S. (1981) Glycosphingolipids in cellular interaction, differentiation, and oncogenesis. Ann. Rev. Biochem. 50, 733–764.CrossRefPubMedGoogle Scholar
  20. Hakomori, S. and Kannagi, R. (1983) Glycosphingolipids as tumor-associated and differentiation markers. J. Natl. Cancer Inst. 71, 231–251.PubMedGoogle Scholar
  21. Hettmer, S., Ladisch, S. and Kaucic, K. (2005) Low complex ganglioside expression characterizes human neuroblastoma cell lines. Cancer Lett. 225, 141–149.CrossRefPubMedGoogle Scholar
  22. Hoon, D.S., Okun, E., Neuwirth, H., Morton, D.L. and Irie, R.F. (1993) Aberrant expression of gangliosides in human renal cell carcinomas. J. Urol. 150, 2013–2018.PubMedGoogle Scholar
  23. Iber, H., Zacharias, C. and Sandhoff, K. (1992) The c-series gangliosides GT3, GT2 and GP1c are formed in rat liver Golgi by the same set of glycosyltransferases that catalyse the biosynthesis of asialo-, a- and b-series gangliosides. Glycobiology 2, 137–142.CrossRefPubMedGoogle Scholar
  24. Keenan, T.W., Morre, D.J. and Basu, S. (1974) Ganglioside biosynthesis. Concentration of glycosphingolipid glycosyltransferases in Golgi apparatus from rat liver. J. Biol. Chem. 249, 310–315.PubMedGoogle Scholar
  25. Klenk (1941) Uber die ganglioside, eine neue gruppe von zukerhaltigen gehirnlipoiden. Z. Physiol. Chem. 273, 76.Google Scholar
  26. Klenk (1942) Neuraminsaure, das spaltprodukt eines neuen gehirnlipoids. Z. Physiol. Chem. 268, 50.Google Scholar
  27. Ladisch, S., Becker, H. and Ulsh, L. (1992) Immunosuppression by human gangliosides: I. Relationship of carbohydrate structure to the inhibition of T cell responses. Biochimica et Biophysica Acta 1125, 180–188.Google Scholar
  28. Ladisch, S., Gillard, B., Wong, C. and Ulsh, L. (1983) Shedding and immunoregulatory activity of YAC-1 lymphoma cell gangliosides. Cancer Res. 43, 3808–3813.PubMedGoogle Scholar
  29. Ladisch, S., Hasegawa, A., Li, R. and Kiso, M. (1995) Immunosuppressive activity of chemically synthesized gangliosides. Biochemistry. 34, 1197–1202.CrossRefPubMedGoogle Scholar
  30. Ladisch, S., Kitada, S. and Hays, E.F. (1987) Gangliosides shed by tumor cells enhance tumor formation in mice. J. Clin. Invest. 79, 1879–1882.CrossRefPubMedGoogle Scholar
  31. Ladisch, S., Li, R. and Olson, E. (1994) Ceramide structure predicts tumor ganglioside immunosuppressive activity. Proc. Natl. Acad. Sci. U.S.A. 91, 1974–1978.CrossRefPubMedGoogle Scholar
  32. Ladisch, S., Ulsh, L., Gillard, B. and Wong, C. (1984) Modulation of the immune response by gangliosides. Inhibition of adherent monocyte accessory function in vitro. J. Clin. Invest. 74, 2074–2081.CrossRefPubMedGoogle Scholar
  33. Ladisch, S., Wu, Z.L., Feig, S., Ulsh, L., Schwartz, E., Floutsis, G., Wiley, F., Lenarsky, C. and Seeger, R. (1987) Shedding of GD2 ganglioside by human neuroblastoma. Int. J. Cancer 39, 73–76.CrossRefPubMedGoogle Scholar
  34. Ledeen, R.W. and Yu, R.K. (1982) Gangliosides: structure, isolation, and analysis. Meth. Enzymol. 83, 139–191.CrossRefPubMedGoogle Scholar
  35. Lengle, E.E., Krishnaraj, R. and Kemp, R.G. (1979) Inhibition of the lectin-induced mitogenic response of thymocytes by glycolipids. Cancer Res. 39, 817–822.PubMedGoogle Scholar
  36. Li, R.X. and Ladisch, S. (1991) Shedding of human neuroblastoma gangliosides. Biochim. Biophys. Acta 1083, 57–64.PubMedGoogle Scholar
  37. Mandon, E.C., Ehses, I., Rother, J., van Echten, G. and Sandhoff, K. (1992) Subcellular localization and membrane topology of serine palmitoyltransferase, 3-dehydrosphinganine reductase, and sphinganine N-acyltransferase in mouse liver. J. Biol. Chem. 267, 11144–11148.PubMedGoogle Scholar
  38. Merritt, W.D., Bailey, J.M. and Pluznik, D.H. (1984) Inhibition of interleukin-2-dependent cytotoxic T lymphocyte growth by gangliosides. Cell. Immunol. 89, 1–10.CrossRefPubMedGoogle Scholar
  39. Offner, H., Thieme, T. and Vandenbark, A.A. (1987) Gangliosides induce selective modulation of CD4 from helper T lymphocytes. J. Immunol. 139, 3295–3305.PubMedGoogle Scholar
  40. Partington, C.R. and Daly, J.W. (1979) Effect of gangliosides on adenylate cyclase activity in rat cerebral cortical membranes. Mol. Pharmacol. 15, 484–491.PubMedGoogle Scholar
  41. Pizzo, P. and Viola, A. (2003) Lymphocyte lipid rafts: structure and function. Curr. Opin. Immunol. 15, 255–260.CrossRefPubMedGoogle Scholar
  42. Portoukalian, J., David, M.J., Shen, X., Richard, M. and Dubreuil, C. (1989) Tumor size-dependent elevations of serum gangliosides in patients with head and neck carcinomas. Biochem. Int. 18, 759–765.PubMedGoogle Scholar
  43. Ritter, G. and Livingston, P.O. (1991) Ganglioside antigens expressed by human cancer cells. Semin. Cancer Biol. 2, 401–409.PubMedGoogle Scholar
  44. Senn, H.J., Orth, M., Fitzke, E., Wieland, H. and Gerok, W. (1989) Gangliosides in normal human serum. Concentration, pattern and transport by lipoproteins. Eur. J. Biochem .181, 657–662.CrossRefPubMedGoogle Scholar
  45. Shurin, G.V., Shurin, M.R., Bykovskaia, S., Shogan, J., Lotze, M.T. and Barksdale, E.M., Jr. (2001) Neuroblastoma-derived gangliosides inhibit dendritic cell generation and function. Cancer Res. 61, 363–369.PubMedGoogle Scholar
  46. Somova, O.G., Tekieva, E.A., Diatlovitskaia, E.V., Bassalyk, L.S. and Bergel’son, L.D. (1991) Ganglioside (GD3) in serum of cancer patients. Vopr. Med. Khim. (Russia) 37, 21–23.Google Scholar
  47. Sorice, M., Parolini, I., Sansolini, T., Garofalo, T., Dolo, V., Sargiacomo, M., Tai, T., Peschle, C., Torrisi, M.R. and Pavan, A. (1997) Evidence for the existence of ganglioside-enriched plasma membrane domains in human peripheral lymphocytes. J. Lipid Res. 38, 969–980.PubMedGoogle Scholar
  48. Sorice, M., Pavan, A., Misasi, R., Sansolini, T., Garofalo, T., Lenti, L., Pontieri, G.M., Frati, L. and Torrisi, M.R. (1995) Monosialoganglioside GM3 induces CD4 internalization in human peripheral blood T lymphocytes. Scand. J. Immunol. 41, 148–156.CrossRefPubMedGoogle Scholar
  49. Steck, T.L. and Dawson, G. (1974) Topographical distribution of complex carbohydrates in the erythrocyte membrane. J. Biol. Chem. 249, 2135–2142.PubMedGoogle Scholar
  50. Svennerholm, L. (1980) Gangliosides and synaptic transmission. Adv. Exp. Med. Biol. 125, 533–544.PubMedGoogle Scholar
  51. Thornton, M.V., Kudo, D., Rayman, P., Horton, C., Molto, L., Cathcart, M.K., Ng, C., Paszkiewicz-Kozik, E., Bukowski, R., Derweesh, I., Tannenbaum, C.S. and Finke, J.H. (2004) Degradation of NF-kappa B in T cells by gangliosides expressed on renal cell carcinomas. J. Immunol. 172, 3480–3490.PubMedGoogle Scholar
  52. Tourkova, I.L., Shurin, G.V., Chatta, G.S., Perez, L., Finke, J., Whiteside, T.L., Ferrone, S. and Shurin, M.R. (2005) Restoration by IL-15 of MHC class I antigen-processing machinery in human dendritic cells inhibited by tumor-derived gangliosides. J. Immunol. 175, 3045–3052.PubMedGoogle Scholar
  53. Wang, R.F., Zeng, G., Johnston, S.F., Voo, K. and Ying, H. (2002) T cell-mediated immune responses in melanoma: implications for immunotherapy. Crit. Rev. Oncol. Hematol. 43, 1–11.CrossRefPubMedGoogle Scholar
  54. Yogeeswaran, G. and Hakomori, S. (1975) Cell contact-dependent ganglioside changes in mouse 3T3 fibroblasts and a suppressed sialidase activity on cell contact. Biochemistry 14, 2151–2156.CrossRefPubMedGoogle Scholar
  55. Yu, R.K. and Ledeen, R. (1969) Configuration of the ketosidic bond of sialic acid. J. Biol. Chem. 244, 1306–1313.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Miroslava Potapenko
    • 1
  • Galina V. Shurin
    • 1
  • Joel de León
    • 2
  1. 1.Department of Pathology, Division of Clinical ImmunopathologyUniversity of PittsburghPittsburghUSA
  2. 2.Center of Molecular ImmunologyHavanaCuba

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