Antitumor effects on mouse melanoma elicited by local secretion of interleukin-12 and their enhancement by treatment with interleukin-18

To investigate the mechanism of the antitumor effect of locally secreted interleukin-12 (IL-12), we introduced the IL-12 p35 and p40 cDNAs into mouse B16 melanoma cells. IL-12 gene-transfected B16 melanoma (B16/IL12) showed marked retardation of tumor growth when implanted subcutaneously into syngeneic mice. In these mice, depletion of not only Natural Killer (NK) cells But also CD8+ T cells diminished the antitumor effect of locally secreted IL-12. Immunohistochemical analysis showed that NK cells and macrophages accumulated more densely at the center and periphery of B16/IL12 tumors than that of parental Bib tumors, whereas CD4+ T cells and CD8+ T cells accumulated sparsely only at the periphery of both transfected and untransfected tumors. Systemic treatment with interleukin-18 (IL-18) markedly inhibited the growth of B16/IL12 but did not influence the tumor growth of parental B16 cells in vivo. These results suggest that local IL-12 secretion can retard the growth of B16 melanoma mediated primarily by NK cells and indirectly by CD8+ cells and that its antitumor effect is augmented by systemic treatment with the novel cytokine IL-18.