Transduction of Genes Coding for a Histocompatibility (MHC) Antigen and for Its Physiological Inducer Interferon-γ in the Same Cell: Efficient MHC Expression and Inhibition of Tumor and Metastasis Growth

The mouse mammary carcinoma TS/A, of BALB/c (H-2d) origin, was transfected with the murine interferon-γ (IFN-γ) gene (Int. J. Cancer 55: 320, 1993). We used IFN-γ transfectants as recipients for a second round of transfections with murine allogeneic class I histocompatibility (H-2b) genes that are modulated by IFN. Transfectants with either gene alone, as well as parent TS/A cells (TS/A-pc), were used as controls. Only double transfectants expressed high levels of the allogeneic H-2b genes, while in H-2b single transfectants the expression was very low (but was induced by treatment with exogenous IFN-γ). The tumorigenic potential of IFN-γ or H-2b single transfectants was reduced in comparison to TS/A-pc. IFN-γ + H-2Kb double transfectants were almost nontumorigenic, while IFN-γ + H-2Db clones gave rise to tumors in about one-half of mice. The experimental metastatic ability of all IFN-γ + H-2b double transfectants was very low. IFN-γ single transfectants were known to induce a strong macrophage response in the host. The expression of allogeneic H-2 antigens added a T-lymphocyte-mediated response that accounted for the lower tumorigenicity of double transfectants. These results show that it is possible to steer the immune response evoked by tumor cells for therapeutic purposes. Moreover, the high H-2 expression obtained in IFN-γ + H-2b double transfectants suggests that single IFN-γ transfectants are ideal recipients for all IFN-sensitive genes. This approach can be used also for other general-purpose inducers of gene expression. Two genes were inserted in the same tumor cell: one coding for an immunogenic product (an allogeneic major histocompatibility complex glycoprotein) and another coding for a potent physiologic inducer of the first one, interferon-γ (IFN-γ). The resulting double transfectants express high levels of the antigenic protein, are less tumorigenic and less metastatic than single transfectants, and stimulate both macrophages and T lymphocytes in vitro and in vivo. Double transfectants can be used for therapeutic vaccinations against the parental tumor; moverover, IFN-γ transfectants are highly effective recipients for IFN-sensitive genes.