Anti-tumor immunity induced by interleukin-12 gene therapy in a metastatic model of breast cancer is mediated by natural killer cells.

An intrahepatic tumor model for metastatic breast cancer was generated in syngeneic mice by direct inoculation of JC cells, a murine mammary adenocarcinoma cell line. Intratumoral administration of a recombinant adenoviral vector expressing the murine Interleukin-12 (ADV-mIL-12) resulted in significant reduction in the tumor volume compared to control vector. Tumor regression was also evident on histopathologic analysis of the liver, where inflammatory changes as opposed to nuclear atypia predominated after IL-12 vector treatment. There was a significant prolongation in the long term survival of IL-12 treated animals, with complete tumor rejection in 40% of the animals. In vivo depletion studies using specific monoclonal antibodies against the various lymphocyte subsets showed a significant reduction in long term survival after natural killer (NK) cell depletion. This suggests that the NK cell is a critical effector in the antitumor effect mediated by IL-12. These results strongly support the potential role of gene mediated cytokine therapy for the treatment of metastatic breast cancer.