Synergistic Suppressive Effect of Double Transfection of Tumor Necrosis Factor‐α and Interleukin 12 Genes on Tumorigenicity of Meth‐A Cells

Department of Internal Medicine, Otaru Ekisaikai Hospital,Shikinai 1-chome, Otaru 047-0031Tumor necrosis factor-α (TNF-α) and interleukin 12 (IL-12), both potent antitumor cytokines, areknown to be involved in the host’s antitumor immune surveillance in tumor bearers, via differentmechanisms. The former enhances the activities of dendritic cells, natural killer/lymphocyte-activated killer (NK/LAK) and cytotoxic T lymphocyte (CTL), while the latter induces Th1-typecellular immunity and enhances the activities of natural killer T (NKT), NK/LAK and CTL. In thepresent study, in the expectation of synergistic actions of these cytokines in stimulating the host’simmune responses, we investigated the feasibility of a cancer vaccine involving double transfectionwith both genes in a murine model. The expression of major histocompatibility complex (MHC)class I, class II and B7.1 on the surface of the double transfectants was enhanced as revealed byFACS analysis. A significant decrease in tumorigenicity was observed in mice inoculated with thedouble transfectants. Cytotoxicity assay revealed that the activities of NK/LAK and CTL fromspleens of mice bearing the double transfectants were enhanced. The induction of tumor-specificimmunity was confirmed by rechallenge with parental Meth-A cells in mice that had rejected thedouble transfectants. Thus, double transfection of TNF-α and IL-12 genes was considered to bringabout synergistic suppressive effects on the tumorigenicity of transfectants through the activationof killer cells by produced cytokines and the enhancement of expression of MHC class I, II andB7.1 molecules.Key words: TNF-α — IL-12 — MHC class I — B7.1 — Cancer gene therapy