Interleukin-18 and the costimulatory molecule B7-1 have a synergistic anti-tumor effect on murine melanoma; Implication of combined immunotherapy forpoorly immunogenic malignancy

Interleukin-18 has been described recently as a cytokine secreted primarily by Kupffer cells. Furthermore, it has been shown that it has significant a nti-tumor effects, which are mediated by T cells and natural killer cells, in a manner similar to interleukin-12. Here, we report the evaluation of th e effects of the systemic administration of interleukin-18 in combination w ith B7-1 (CD80) expressed on tumor cells [interleukin-18 + B7-1] on the gro wth of murine B16 melanoma in vivo. After the subcutaneous inoculation of B 16 melanoma, B16 tumors grew progressively in immunocompetent syngeneic C57 BL/6 mice. Mice treated with either interleukin-18 or immunized with B7-1-t ransduced B16 did not demonstrate significant anti-tumor effect. The combin ation of the two treatments, however, resulted in dramatic suppression of m elanoma formation, tumor growth, and a significant improvement in survival. Inhibitory effects of [interleukin-18 + B7-1] on lung metastasis in mice w ere also detected. Additionally, mice treated with [interleukin-18 + B7-1] showed an increase of natural killer cytotoxicity and interferon-gamma prod uction in vivo. Unlike [interleukin-18 + B7-1], [interleukin-12 + B7-1] did not have a strong anti-tumor effect against B16 melanoma. Histologic chara cterization after the [interleukin-18 + B7-1] treatment confirmed the infil tration of natural killer cells into the tumor, suggesting that natural kil ler cells may be involved in the [interleukin-18 + B7-1]-induced anti-tumor effect. This finding was confirmed by showing that depletion of NK1.1(+) c ells before immunization inhibits the [interleukin-18 + B7-1]-induced anti- tumor effect. Depletion of CD3(+) cells in vivo also decreased the anti-tum or effect of [interleukin-18 + B7-1], suggesting the importance of CD3(+) T cells. Collectively, combination with interleukin-18 and B7-1 expression h as synergistic anti-tumor effects against B16 murine melanoma.