The long term goal of this project is to characterize suppression of antitumor immune responses by tumor gangliosides in vivo. The hypothesis underlying this work is that specific gangliosides are shed by tumors, act as intercellular signaling molecules, block the cellular immune response, and protect tumor cells from host immune destruction. Findings of significant shedding of potent immunosuppressive activity of human neuroblastoma tumor gangliosides in vitro, and of inhibition of murine allogeneic cellular immune responses in vivo by these molecules, lay the foundation for studies to demonstrate suppression of syngeneic antitumor immune responses by tumor gangliosides. To accomplish this goal, neuroblastoma tumor gangliosides homogenous in both carbohydrate and ceramide structure will be obtained on a large (preparative) scale by two complementary approaches--by isolation from LAN-5 cells and by chemical synthesis of selected species. Molecular structures are being confirmed by MS and chemical methods. Tumor gangliosides will be studied to fully characterize their effects on the human cellular immune response in vitro (antigen-induced lymphoproliferation, mixed lymphocyte response, T cell cytotoxicity, and natural cytotoxicity), to determine which functions are altered by these molecules and to identify potent molecular species for in vivo studies. The in vivo studies will be performed in two murine syngeneic tumor systems, the FBL erythroleukemia and the B78H1 melanoma, to test the effect of tumor gangliosides upon both the afferent and efferent phases of the cellular immune response against a syngeneic tumor. These studies directly test the hypothesis that gangliosides shed by tumors inhibit host cellular immune responses to tumor cells in vivo.
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