Interleukin-18 gene transfer increases antitumor effects of suicide gene therapy through efficient induction of antitumor immunity

To increase the antitumor effects of cytosine deaminase (AdCD) gene therapy and induce more potent antitumor immunity, Th1 cytokine interleukin-18 enc oded adenovirus (AdIL18) was combined with adenovirus encoding CD (AdCD) fo r the therapy of established murine B16 melanoma. combination therapy of th e tumor-bearing mice with AdlL18 and AdCD/SFC inhibited the growth of the s ubcutaneous 816 tumors more significantly, compared with AdlL18 or AdCD/SFC alone. In vivo depletion analysis with anti-CD4, anti-cog or anti-NK 1. 1 McAb illustrated that both CD8(+) T cells and CD4(+) T cells played key rol es in the augmented antitumor response of the combined therapy. Peptide/MHC tetramer represents a powerful and general tool for rapid, highly sensitiv e, and direct analysis of antigen-specific T cells. In this study, we prepa red H-2K(b)/TRP2(180-188) tetramer, which was demonstrated to bind H-2K(b)- restricted, 816 melanoma- specific CD8(+) T cells. B16 specific H-2K(b)/TRP 2(180188)tetramer was used to stain the tumor-specific CD8(+) T cells and t he results showed that CD8(+) tetramer T cells were about 3-5% of the splen ic CD8(+) T cells derived from tumor-bearing mice after combined therapy. T he CTL cytotoxicity was markedly induced in mice after combined therapy, su ggesting efficient induction of tumor-specific CD8(+) T cells after combine d gene therapy with AdCD/5FC/AdIL18. IL-18 gene transfer could significantl y augment the cytotoxicity of NK cells and macrophages, and increase the pr oduction of interleukin-2 and interferon-gamma, as compared with treatments with AdCD/SFC, AdlacZ/5FC or PBS. These data suggested that in vivo IL-18 gene transfer could augment the antitumor effects of CD suicide gene therap y through efficient induction of antitumor immunity.