One mechanism by which macrophages can function in vivo to restrict neoplastic growth is direct cytolysis of tumor cells. Although tumor cell cytolysis by activated macrophages displays many characteristics of classic receptor/ligand interactions, the tumor cell surface moieties recognized by macrophages have not been identified. Previous studies in this laboratory have found that sensitivity to cytolysis by macrophages is not an obligate outcome of cellular transformation. Furthermore, among cultured cell lines, transformed by the same oncogenic virus and from the same strain of mice, resistance to macrophage cytolysis in vitro is predictive of progressive tumor growth in vivo. Specific goals of this application are to: (1) determine whether H-2-linked genes or endogenous retroviral genes function to control the macrophage-resistant phenotype of transformed cells; (2) determine, at a molecular level, the mechanisms by which resistance to macrophage cytolysis occurs in different transformed cells; (3) assess the importance of the macrophage-resistant phenotype in the development of progressing tumors in vivo; and (4) identify the tumor cell surface ligands recognized by cytolytic macrophages. The overall goal of these studies is to learn, from an immunologist's point of view, which genotypic and phenotypic changes occur that allow the cell to escape normal homeostatic mechanisms during the development of a neoplastic cell. (IB)