Ceramide structure predicts tumor ganglioside immunosuppressive activity.
Molecular determinants of biological activity of gangliosides are generally believed to be carbohydrate in nature. However, our studies of immunomodulation by highly purified naturally occurring tumor gangliosides provide another perspective: while the immunosuppressive activity of gangliosides requires the intact molecule (both carbohydrate and ceramide moieties), ceramide structure strikingly influences ganglioside immunosuppressive activity. Molecular species of human neuroblastoma GD2 ganglioside in which the ceramide contains a shorter fatty acyl chain (C16:0, C18:0) were 6- to 10-fold more active than those with a longer fatty acyl chain (C22:0/C24:1, C24:0). These findings were confirmed in studies of ceramide species of human leukemia sialosylparagloboside and murine lymphoma GalNAcGM1b. Gangliosides that contain shorter-chain fatty acids (and are most immunosuppressive) are known to be preferentially shed by tumor cells. Therefore, the results suggest that the tumor cell is optimized to protect itself from host immune destruction by selective shedding of highly active ceramide species of gangliosides.
Ladisch
S
S
Center for Cancer and Transplantation Biology, Children's National Medical Center, Washington, DC 20010.
Li
R
R
Olson
E
E
D000818:Animals; D001921:Brain / Q000276:immunology; D001923:Brain Chemistry; D002240:Carbohydrate Sequence; D002518:Ceramides / Q000737:chemistry* / Q000276:immunology / Q000494:pharmacology; D005732:Gangliosides / Q000737:chemistry* / Q000276:immunology / Q000494:pharmacology; D006801:Humans; D007108:Immune Tolerance; D007166:Immunosuppressive Agents / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000737:chemistry* / Q000276:immunology*; D009447:Neuroblastoma / Q000737:chemistry / Q000276:immunology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000737:chemistry / Q000276:immunology
D002518:Ceramides; D005732:Gangliosides; D007166:Immunosuppressive Agents; C019403:ganglioside, GD2