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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA028139-11
Application #
3168021
Study Section
Experimental Immunology Study Section (EI)
Project Start
1980-09-30
Project End
1993-06-30
Budget Start
1991-07-12
Budget End
1992-06-30
Support Year
11
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Weizmann Institute of Science
Department
Type
DUNS #
City
Rehovot
State
Country
Israel
Zip Code
76100
Porgador, A; Tzehoval, E; Vadai, E et al. (1995) Combined vaccination with major histocompatibility class I and interleukin 2 gene-transduced melanoma cells synergizes the cure of postsurgical established lung metastases. Cancer Res 55:4941-9
Yamit-Hezi, A; Plaksin, D; Eisenbach, L (1994) c-fos and c-jun overexpression in malignant cells reduces their tumorigenic and metastatic potential, and affects their MHC class I gene expression. Oncogene 9:1065-79
Fitzer-Attas, C; Eldar, H; Eisenbach, L et al. (1994) The expression of PDGF-alpha but not PDGF-beta receptors is suppressed in Swiss/3T3 fibroblasts over-expressing protein kinase C-alpha. FEBS Lett 342:165-70
Porgador, A; Bannerji, R; Watanabe, Y et al. (1993) Antimetastatic vaccination of tumor-bearing mice with two types of IFN-gamma gene-inserted tumor cells. J Immunol 150:1458-70
Katz, A; Shulman, L M; Revel, M et al. (1993) Combined therapy with IL-6 and inactivated tumor cells suppresses metastasis in mice bearing 3LL lung carcinomas. Int J Cancer 53:812-8
Fitzer-Attas, C; Feldman, M; Eisenbach, L (1993) Expression of functionally intact PDGF-alpha receptors in highly metastatic 3LL Lewis lung carcinoma cells. Int J Cancer 53:315-22
Plaksin, D; Baeuerle, P A; Eisenbach, L (1993) KBF1 (p50 NF-kappa B homodimer) acts as a repressor of H-2Kb gene expression in metastatic tumor cells. J Exp Med 177:1651-62
Katz, A; Shulman, L M; Porgador, A et al. (1993) Abrogation of B16 melanoma metastases by long-term low-dose interleukin-6 therapy. J Immunother Emphasis Tumor Immunol 13:98-109
Porgador, A; Tzehoval, E; Vadai, E et al. (1993) Immunotherapy via gene therapy: comparison of the effects of tumor cells transduced with the interleukin-2, interleukin-6, or interferon-gamma genes. J Immunother Emphasis Tumor Immunol 14:191-201
Porgador, A; Gansbacher, B; Bannerji, R et al. (1993) Anti-metastatic vaccination of tumor-bearing mice with IL-2-gene-inserted tumor cells. Int J Cancer 53:471-7

Showing the most recent 10 out of 30 publications