Adenovirus-mediated lymphotactin gene transfer improves therapeutic efficacy of cytosine deaminase suicide gene therapy in established murine colon carcinoma

Lymphotactin (Ltn) is the sole member of C chemokines which attracts T cell s and NK cells specially. Ltn gene was transferred in vivo to improve the a ntitumor efficacy of cytosine deaminase (CD) gene therapy. Upregulation of CD80 and CD54 on murine CT26 colon carcinoma cells was observed after combi ned transfection with adenovirus encoding GD (AdCD) and adenovirus encoding murine Ltn (AdLtn) followed by administration of 5-fluorocytosine (5FC) in vitro. AdCD/5FC treatment also increased the expression of CD95 and induce d obvious apoptosis of CT26 cells. After combined treatment with AdLtn and AdCD/5FC, the preestablished murine model with subcutaneous CT26 colon carc inoma exhibited most significant tumor growth inhibition, and four of eight tumor-bearing mice were tumor free, while tumors in other mice grew more p rogressively. Examination of lymphocyte infiltration and cytokine gene expr ession in tumor tissue revealed that tumors from AdLtn/AdCD/5FC-or AdLtn-tr eated mice were heavily infiltrated with CD4(+), CD8(+) T cells and NK cell s, and IL-2 and IFN-gamma mRNA expression were present in parallel with T c ell and NK cell infiltration. Splenic NK and CTL activities increased signi ficantly after the combination therapy. In vivo depletion analysis showed t hat NK cells, CD4(+) T cells and CD8(+) T cells participated in the antitum or effect of the host with CD8(+) T cells being the main T cell subset resp onsible for the enhanced antitumor immune response. These findings suggeste d that increased immunogenicity and induction of apoptosis of the tumor cel ls, and efficient induction of local and systemic antitumor immunity of the host might contribute to the enhanced antitumor effects of the combined Lt n and CD suicide therapy.