The potent antitumor effects of combined p16 gene and GM-CSF gene therapy through efficient induction of antitumor immunity

Purpose: Tumor suppressor gene therapy and cytokine gene therapy have limit ed antitumor effects when used alone. Thus, in the present study, we invest igated the antitumor potentials of the combined transfer of the p16 tumor s uppressor gene and the murine granulocyte-macrophage colony-stimulating fac tor (GM-CSF) gene. Methods: The adenovirus-harboring p16 gene (Adp16) and a denovirus-harboring: GM-CSF (AdGMCSF) gene were utilized for the treatment of established tumors in vivo. The mice were inoculated s.c. with Renca ren al carcinoma cells and 3 days later received an intratumoral injection of A dp16 in combination with AdGMCSF. Results: The results demonstrated that tu mor-bearing mice treated with Adp16 and AdGMCSF showed more potent inhibiti on of tumor growth and a prolonged survival period than mice treated with A dp16, AdGMCSF, adenovirus-expressing beta -galactosidase or PBS (P < 0.01). Treatments of the mice with Adp16 alone or AdGMCSF alone also showed obvio us antitumor effects as compared with those mice treated with PBS (P < 0.05 ). After combined p16 and AdGMCSF gene therapy, the expression of H-2K(d) a nd Fas molecules on freshly isolated tumor cells increased markedly, and mo re CD4+ T cells and CD8+ T cells infiltrated in the tumor sites. The cytoto xicity of natural killer cells and specific cytotoxic T lymphocytes increas ed more significantly after the combined therapy. Conclusions: Our results demonstrated that combination p16 gene and GM-CSF gene therapy could inhibi t the growth of established tumors in mice more significantly through effic ient induction of antitumor immunity.