Synergistic antitumor effects of interleukin-12 gene transfer and systemicadministration of interleukin-18 in a mouse bladder cancer model

We introduced the interleukin-12 (IL-12) gene into the mouse bladder cancer cell line (MBT2) to establish sublines that secrete bioactive IL-12. IL-12 -secreting MBT2 (MBT2/IL-12) sublines were completely rejected when subcuta neously implanted into immunocompetent syngeneic C3H mice. Although this an titumor effect did not change when IL-12-secreting cells were injected into immunodeficient mice whose CD8(+) T or CD4(+) T cells had been depleted by the corresponding antibody, it was abrogated when natural killer cells wer e depleted by anti-asialoGM1 antibody. In addition, when parental MBT2 cell s mixed with MBT2/IL-12 cells were subcutaneously injected into mice, admir ed MBT2/IL-12 inhibited the growth of the parental tumor. Furthermore, this antitumor effect was enhanced by systemic IL-18 administration. This syner gism was abrogated when the mice were treated with interferon-gamma-neutral izing antibody in vivo. In conclusion, local secretion of IL-12 led to effe ctive antitumor activity that was enhanced by systemic administration of IL -18. Interferon-gamma plays an important role in the synergism of IL-12 gen e transduction and systemic administration of IL-18.