Secreted type of modified interleukin-18 gene transduced into mouse renal cell carcinonia cells induces systemic tumor immunity

Purpose: Interleukin (IL)-18 is a novel cytokine that has been identified a s a strong interferon-gamma inducer. IL-18 has bioactivity similar to that of IL-12 and demonstrates antitumor effects. Since IL-18 does not have a si gnal sequence, we constructed the gene, consisting of the signal sequences of interferon-beta and mature IL-18 complementary (c) DNA. The modified gen e was subsequently transduced into a mouse renal cell carcinoma cell line t o induce IL-18 secretion from tumor cells to establish whether this IL-18 s ecreting tumor cell line may induce systemic tumor immunity. Materials and Methods: Modified IL-18 cDNA consisting of the signal sequenc es of interferon-beta and mature type of IL-18 cDNA was constructed by the overlap extension method. The modified and original IL-18 cDNA was transduc ed 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 d etermined. Direct antitumor and tumor vaccine effects were investigated in syngeneic Balb/c mice. To determine the mechanism of the antitumor effect i mmunodeficient mice were challenged with IL-18 secreting RenCa cells. Results: Although the modified and original IL-18 genes transduced RenCa sh owed almost the same level of IL-18 messenger RNA expression, only RenCa ce lls transduced with modified IL-18 gene secreted IL-18 into the culture sup ernatant and were completely rejected when transplanted into syngeneic mice . T lymphocytes were involved in this antitumor effect. Moreover, the modif ied IL-18 transduced RenCa induced tumor vaccine effect against parental Re nCa cells injected at a distant site. Conclusions: Immune gene therapy using modified IL-18 cDNA appears to be ef fective and IL-18 secreting cancer cells may be a candidate for tumor vacci ne therapy.