Secreted type of modified interleukin-18 gene transduced into mouse renal cell carcinoma cells induces systemic tumor immunity.
OBJECTIVE
Interleukin (IL)-18 is a novel cytokine that has been identified as 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 signal sequence, we constructed the gene, consisting of the signal sequences of interferon-beta 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.


METHODS
Modified IL-18 cDNA consisting of the signal sequences 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 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.


RESULTS
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.


CONCLUSIONS
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.
Hara
S
S
Department of Urology, Kobe University School of Medicine, Kobe, Japan.
Nagai
H
H
Miyake
H
H
Yamanaka
K
K
Arakawa
S
S
Ichihashi
M
M
Kamidono
S
S
Hara
I
I
D000818:Animals; D019496:Cancer Vaccines; D002292:Carcinoma, Renal Cell / Q000628:therapy*; D005240:Feasibility Studies; D005260:Female; D015316:Genetic Therapy; D020382:Interleukin-18 / Q000235:genetics*; D007680:Kidney Neoplasms / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
D019496:Cancer Vaccines; D020382:Interleukin-18