Interleukin-12 administration is more effective for preventing metastasis than for inhibiting primary established tumors in a murine model of spontaneous hepatic metastasis

Purpose. The effect of interleukin-12 (IL-12) on tumor growth at the primary site and its therapeutic efficacy against metastasis were examined using a model of spontaneous hepatic metastasis. Methods. IL-12 was peritumorally injected into RL♂1 tumor-bearing BALB/c male mice at the different tumor stage. Results. Striking inhibition of hepatic metastasis in both athymic and euthymic mice was induced by the administration of IL-12 irrespective of the stage of tumor progression. In contrast, IL-12 failed to produce any antitumor effect in athymic mice which lack conventional T cells. These results suggest that the antitumor effect of IL-12 is mediated mainly by T cells, and that the antimetastatic effect is mediated mainly by natural killer (NK) and/or NKT cells. Next we examined the direct effect of IL-12 on these cells. IL-12-induced T-cell proliferation was remarkably augmented in the early stage, then decreased dramatically in the advanced stage, while IL-12-induced cytotoxic activity, mediated by NK and NKT cells, was not attenuated even in the advanced stage. This dissociation in IL-12 responsiveness appeared to be the reason for the remarkable antimetastatic effect but insufficient antitumor effect of IL-12 in the advanced stage. Conclusion. The findings of this study support the clinical use of IL-12 for immunotherapy against either occult or evident liver metastasis.