SECRETED TYPE OF MODIFIED INTERLEUKIN-18 GENE TRANSDUCED INTO MOUSE RENAL CELL CARCINOMA CELLS INDUCES SYSTEMIC TUMOR IMMUNITY

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Abstract
Interleukin (IL)-18 is a novel cytokine that has been identified as a strong interferon-γ inducer. IL-18 has bioactivity similar to that of IL-12 and demonstrates antitumor effects. Since IL-18 does not have a signal sequence, we constructed the gene, consisting of the signal sequences of interferon-β and mature IL-18 complementary (c) DNA. The modified gene was subsequently transduced into a mouse renal cell carcinoma cell line to induce IL-18 secretion from tumor cells to establish whether this IL-18 secreting tumor cell line may induce systemic tumor immunity. Modified IL-18 cDNA consisting of the signal sequences of interferon-β and mature type of IL-18 cDNA was constructed by the overlap extension method. The modified and original IL-18 cDNA was transduced into the RenCa mouse renal cell carcinoma cell line. Expression of IL-18 messenger RNA and concentration of IL-18 in the culture supernatant were determined. Direct antitumor and tumor vaccine effects were investigated in syngeneic Balb/c mice. To determine the mechanism of the antitumor effect immunodeficient mice were challenged with IL-18 secreting RenCa cells. Although the modified and original IL-18 genes transduced RenCa showed almost the same level of IL-18 messenger RNA expression, only RenCa cells transduced with modified IL-18 gene secreted IL-18 into the culture supernatant and were completely rejected when transplanted into syngeneic mice. T lymphocytes were involved in this antitumor effect. Moreover, the modified IL-18 transduced RenCa induced tumor vaccine effect against parental RenCa cells injected at a distant site. Immune gene therapy using modified IL-18 cDNA appears to be effective and IL-18 secreting cancer cells may be a candidate for tumor vaccine therapy.