Gangliosides from human melanoma tumors impair dendritic cell differentiation from monocytes and induce their apoptosis.
Gangliosides are ubiquitous membrane-associated glycosphingolipids, which are involved in cell growth and differentiation. Most tumor cells synthesize and shed large amounts of gangliosides into their microenvironment, and many studies have unraveled their immunosuppressive properties. In the present study we analyzed the effects of GM3 and GD3 gangliosides, purified from human melanoma tumors, on the differentiation of monocyte-derived dendritic cells (MoDC). At concentrations close to those detected in the sera from melanoma patients, both gangliosides dose-dependently inhibit the phenotypic and functional differentiation of MoDC, as assessed by a strong down-regulation of CD1a, CD54, CD80, and CD40 Ags and impaired allostimulatory function on day 6 of culture. Furthermore, GM3 and GD3 gangliosides decreased the viable cell yield and induced significant DC apoptosis. Finally, addition of GD3 to differentiating DC impaired their subsequent maturation induced by CD154. The resulting DC produced low amounts of IL-12 and large amounts of IL-10, a cytokine pattern that might hamper an efficient antitumor immune response. In conclusion, the results demonstrate that gangliosides impair the phenotypic and functional differentiation of MoDC and induce their apoptosis, which may be an additional mechanism of human melanoma escape.
Péguet-Navarro
Josette
J
Institut National de la Santé et de la Recherche Médicale, Unité 346, Hôpital E. Herriot, Lyon, France. peguet@lyon.inserm.fr
Sportouch
Myriam
M
Popa
Iuliana
I
Berthier
Odile
O
Schmitt
Daniel
D
Portoukalian
Jacques
J
D000951:Antigens, Neoplasm / Q000302:isolation & purification / Q000502:physiology*; D017209:Apoptosis / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000378:metabolism / Q000473:pathology*; D015232:Dinoprostone / Q000096:biosynthesis; D005679:G(M3) Ganglioside / Q000302:isolation & purification / Q000502:physiology*; D005732:Gangliosides / Q000302:isolation & purification / Q000502:physiology*; D006131:Growth Inhibitors / Q000276:immunology / Q000302:isolation & purification / Q000502:physiology*; D006801:Humans; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D008545:Melanoma / Q000737:chemistry / Q000276:immunology*; D009000:Monocytes / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D015854:Up-Regulation / Q000276:immunology
D000951:Antigens, Neoplasm; D005679:G(M3) Ganglioside; D005732:Gangliosides; D006131:Growth Inhibitors; D008024:Ligands; D023201:CD40 Ligand; D018664:Interleukin-12; C049132:9-O-acetyl-GD3 ganglioside; D015232:Dinoprostone