IFN-γ-inducing factor/IL-18 administration mediates IFN-γ- and IL-12- independent antitumor effects

We evaluated the mechanism of the antitumor effect of mouse rIFN-γ- inducing factor/IL-18 protein on the growth of mouse tumor cell lines in vivo. Mice received IL-18 before or after challenged with CL8-1, a mouse melanoma cell line. Both regimens significantly suppressed tumor growth and reduced the number of mice with growth of tumor from 60% (3/5) to 20% (1/5). Furthermore, IL-18 administered before and after tumor inoculation completely abrogated the establishment of CL8-1 in all animal. IL-18 administration also significantly suppressed the growth of MCA205, a sarcoma cell line, even when treatment was delayed to 7 days following tumor inoculation. Although IL- 18/IL-12 combination therapy had the most significant and immediate antitumor effects, many mice so treated succumbed with markedly elevated serum IFN-γ levels. The antitumor effects of IL-18 were abrogated almost completely when NK cells were eliminated using anti-asialo GM1 Ab administration, but only marginally impaired in IFN-γ or IL-12 gene-disrupted mice. Immunohistochemical staining revealed that the number of the CD8⁺ T cells, but not CD4⁺ T cells, found at the tumor site was reduced in animals treated with IL-18. These results indicated that IL-18 has potent antitumor effects mediated by CD4⁺ T cells and NK cells, but in IFN-γ- and IL-12-independent pathways.