Effects of immunotherapy of IL-6 and IL-15 plasmids on transmissible venereal tumor in beagles

Canine transmissible venereal tumor (CTVT) is a tumor with low MHC antigen expression and is an ideal tumor model for studying the interactions between host immunity and cancer cells. CTVTs produce high concentrations of TGF-β to hamper the host immune responses and facilitate their growth progression. However, during the later stages of tumor progression, tumor-infiltrating lymphocytes secrete IL-6. This cytokine antagonizes TGF-β and restores the IFN-γ activities in promoting MHC antigen expression, and the NK cytotoxicity that has been repressed by TGF-β is also activated. In this study, we applied combinatory treatment of IL-6 plasmid and IL-15 plasmid (pIL-6/pIL-15) to CTVT-bearing beagles. IL-6 was used as an anti-TGF-β cytokine; IL-15 was used to promote NK- and CTVT-specific cytotoxicity. After intratumoral pIL-6/pIL-15 delivery mediated by electroporation, MHC antigen expression on CTVT cells was dramatically increased from in less than 5.9% to up to 34% of the tumor cells. The proportion of CD8+ T cells infiltrating the tumor was also significantly elevated from 6.96 ± 0.23% to 21.63 ± 5.40%. In addition, the tumor-specific cytotoxicity was enhanced along with a marked increase in tumor-specific IFN-γ-producing cells. These immune responses are believed to be the important forces driving the tumor towards regression. The results indicate that pIL-6/pIL-15 combinatory immunotherapy may facilitate a promising and effective means of treating tumors.