Our recent studies indicate that the oncogenes of DNA viruses differ in their abilities to induce, in the cells they transform, susceptibility to destruction by host celular immune defenses (cytolytic susceptibility). It has also been found that the cytolytic susceptible transformed cell phenotype may be actively regulated by the function of a single viral oncogene. Expression of this oncogene-induced cell phenotype is independent of oncogene transforming activity and of target cell surface expression of histocompatibility antigens and is also apparently unrelated to cell surface expression of oncogene-encoded products. The independent and combined activities of different types of oncogenes that determine susceptibility or resistance of transformed cells to destruction by host mononuclear inflammatory cells will be defined using natural killer cells, activated macrophages and cytotoxic T lymphocytes (effector cells). The mechanisms by which oncogenes regulate susceptibility and resistance to the cytolytic activities of such effector cells will be studied by examining the effects of oncogene expression on (a) transformed cell membrane targets of effector cells, on (b) transformed cell induction of host cytotoxic inflammatory responses and on (c) elaboration by transformed cells of products that effect killer cell migration and function. Transient oncogene expression assays (by protoplast fusion and microinjection) will be used to study effects of oncogene products on cellular cytolytic susceptibility independent of transformation and to develop strategies for cloning transformed cell gene(s) that regulate neoplastic cell cytolytic susceptibility. Studies of in vivo tumor induction by oncogene-transformed cells in hosts with different abilities to mount a cell-mediated immune response will be performed to evaluate the relevance of in vitro observations for tumorigenicity. Attempts will also be made to alter tumorigenicity by introducing into transformed cells oncogenes with known in vitro effects on the cytolytic susceptible transformed cell phenotype. These studies of oncogene functions, as they affect interactions between neoplastic cells and anti-neoplastic host cellular immune defenses should provide new insights into reasons for tumor progression in the immunocompetent host.
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