Antitumor activity of interleukin-18 against the murine T-cell leukemia/lymphoma EL-4 in syngeneic mice

Interleukin (IL)-18 induces interferon (IFN)-gamma production by T cells and natural killer (NK) cells, and augments NK cell activity in mouse spleen cell cultures. It has recently been demonstrated that in vivo administration of IL-18 to mice results in considerable antitumor effects against syngeneic Meth A sarcoma. In this study, the antitumor effects of IL-18 against murine T-cell leukemia (EL-4) were evaluated. EL-4 proliferation was resistant in vitro to IL-18 and IFN-gamma. When 4 x 10(6) EL-4 cells were transplanted intravenously, the antitumor effects of IL-18 were not pronounced, and only a slight prolongation of the mean survival times was observed. The antitumor effects of IFN-gamma were even less apparent than those of IL-18. However, when mice were transplanted intravenously with 5 x 10(5) EL-4 cells, the extent of experimental visceral dissemination of EL-4 was markedly reduced in mice treated subcutaneously with IL-18. resulting in an increase in survival time with some mice even cured. Although IL-18 was highly effective at inhibiting the development of EL-4 lymphoma dissemination in C57BL/6 mice. it could not inhibit the development of dissemination in mutant C57BL/6 beige (bg/bg) mice lacking NK cell activity. The efficacy of IL-18 was also significantly reduced in nude mice lacking T cells. These results suggest that antitumor efficacy of IL-18 is mediated primarily by NK cells, but that T cells are also required for the complete antitumor efficacy of IL-18.