Gangliosides are sialic acid-containing glycosphingolipids found primarily on the cell surface. We will test the hypothesis that specific highly purified and molecularly characterized individual human tumor gangliosides suppress normal cellular immune function, thereby possibly accounting for the abrogation of host immune responses which is frequently observed in cancer and may contribute to tumor progression. This hypothesis is based upon (i) previous findings and those of others that gangliosides are shed in significant quantities by tumor cells into the peripheral circulation of the host in vivo, and (ii) our preliminary data that certain gangliosides (e.g., the neuroblastoma-derived disialoganglioside GD2) have highly potent immunosuppressive activity in vitro. Gangliosides will be isolated from the human tumor neuroblastoma, and from normal brain tissue, and will be highly purified by a combination of methods including a newly developed simple solvent partition method which quantitatively recovers gangliosides from small samples. Individual gangliosides will be isolated by preparative thin layer chromatography and reverse-phase high-pressure liquid chromatography. The complete structure of the individual gangliosides will be determined by a new mass spectroscopic method and by biochemical methods. The immunosuppressive activity of these highly purified individual gangliosides will be assessed in the human antigen-induced lymphoproliferation assay, which measures the generation phase of the cellular immune response. The inhibitory activity of the individual tumor gangliosides, of the simplified glycolipids obtained by enzymatic degradation, and of purified individual brain gangliosides will be determined. Comparison of the relative activities of these molecular species will allow the particular molecular characteristics associated with the expected marked inhibitory activity of certain neuroblastoma tumor gangliosides to be determined. These proposed studies are directed towards our long-term objectives of fully elucidating the biological significance, and understanding the molecular structural bases, of activity of gangliosides which are shed by tumors. The findings obtained by our proposed studies will increase our knowledge of immunoregulatory mechanisms in cancer, and may lead to the development of new approaches to the treatment of neuroblastoma and possibly other tumors.
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