A long-term objective of the project is to investigate the feasibility of immunotherapy of metastasis, using as immunogens inactivated tumor cells which were transfected with major histocompatibility complex (MHC) genes. This approach derives from demonstration that high-metastatic clones from murine tumors differ from low- (or non-) metastatic clones of the same tumors, in manifesting impaired expression of class I antigens of the MHC system (lack of H-2K expression) and that transfection with the H-2K genes converted metastatic to nonmetastatic phenotypes, as a function of the acquisition of H-2K restricted immunogenic potency. Studies will therefore be conducted which are aimed at increasing the immunogenic potency of the transfected tumor cells, and the application of such transfectant for immuno-prevention of metastasis. Attempts towards this goal will consist of studies aimed at increasing the cell surface expression of H-2K genes, by co-transfecting tumor cells with a) syngeneic H-2K genes driven by different promoters and beta-2 macroglobulin genes; b) syngeneic H-2K genes and allogeneic genes and c) syngeneic H-2K genes and/or cytokines such as gamma-IFN. Such gene-inserted cells will be used, following X-ray and mitomycin inactivation, as immunogens, to elicit in tumor excised animals T cell response against metastatic growth. These studies will parallel the investigation of the molecular basis for the impaired expression of class I (H-2K) genes on cells of metastatic clones of murine tumors.
The specific aim here is to determine whether the suppression of H-2K expression in metastatic clones derives from a) rearrangements or mutations in the H-2 genes, b) mutation in the promoter-enhancer region of the MHC genes, c) trans-acting suppressor proteins or lack of trans-acting activating proteins, d) cis-acting enhancer-suppressor domain, or e) differential state of methylation of MHC. Having demonstrated that the c-fos gene products are involved in up-regulation of MHC genes, a) what regulates c-fos expression, b) whether c-fos activates MHC gene expression by its product generating complexes with API-type proteins (products of the jun protein oncogene family), which bind to the MHC enhancer elements will be studied.
Showing the most recent 10 out of 30 publications
