Macrophages, in response to gamma-interferon and LPS, acquire the ability to bind and lyse tumor cells but not normal cells. Amplification of this phenomenon may provide a useful modality for the treatment of cancer. The mechanism by which macrophages acquire tumoricidal ability is poorly understood. Moreover, the components of tumor cell surfaces recognized by macrophages are not known. Considerable data indicate that carbohydrates on tumor cell surfaces participate directly in recognition by macrophages. A major objective of this proposal is to determine if specific carbohydrates which are expressed on the surface as a result of oncogenic transformation are the structures recognized by macrophages. To accomplish this objective, glycopeptides will be purified from tumor cells and from glycoproteins of defined oligosaccharide structure. The ability of these glycopeptides to inhibit tumor cell binding and lysis by activated mouse peritoneal macrophages will be examined. The emphasis of this work will be on correlating inhibitory ability with specific oligosaccharide structural features. The presence of specific receptors on the macrophage surface for carbohydrates which are inhibitory will be assayed for by surface binding studies using iodinated glycopeptides. Should receptors be identified, it will be determined if their surface expression correlates with the acquisition of tumoricidal activity in response to gamma-interferon. Biochemicl data indicate that the surface organization of the ganglioside GM1 and of the neutral glycolipid asialo GM1 is altered by macrophage activation. These changes could be related to the mechanism of activation and could be essential for effective tumor cell interactions. The second major objective of this proposal is to study the behavior of macrophage glycolipids in more detail. Cytochemical studies will be performed to determine if the biochemical data reflect changes in glycolipid surface distribution or intracellular localization. To assess the importance of gangliosides and neutral glycolipids in the development of tumoricidal activity, GM1 and asialo GM1 will be removed (""""""""modulated"""""""") from the apical surface by plating macrophages on surfaces coated with choleragenoid and anti-asialo GM1 antibodies. The ability of these macrophages to respond to Gamma-interferon, and to bind and lyse tumor cells will be examined. This method will also be used to determine if GM1 and asialo GM1 associate with specific proteins on the macrophage surface.
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