Therapeutic Adenovirus Vaccine Combined Immunization with IL-12 Induces Potent CD8(+) T Cell Anti-Tumor Immunity in Hepatocellular Carcinoma

SIMPLE SUMMARY: Hepatocellular carcinoma is a kind of tumor with a high malignant degree and mortality rate, and there is no effective treatment method. Currently, immunotherapy has shown good prospects in treating hepatocellular carcinoma. As an important approach of immunotherapy, the vaccine has become an attractive method for tumor treatment. This study developed an adenovirus vaccine containing tumor antigen glypican-3 and adjuvant interleukin 12. The subcutaneous tumor model was intramuscularly immunized three times with vaccines at a ten-day interval. Compared with the control group, the proliferation of CD 8(+) T cell, the induction of multifunctional CD 8(+) T cell and dendritic cells, and cytotoxic T lymphocyte activity were significantly increased in the combined immunization group, and the growth of tumor was inhibited obviously. The therapeutic effect of the vaccine of glypican-3 and interleukin 12 mainly depends on the anti-tumor effect of CD 8(+) T cells mediated by dendritic cells. Likewise, this vaccine also showed a good therapeutic effect in the lung metastasis model of hepatocellular carcinoma. Therefore, the adenovirus vaccine of glypican-3 and interleukin 12 might become a potential way to treat hepatocellular carcinoma. ABSTRACT: Hepatocellular carcinoma (HCC) is one of the cancers with the highest morbidity and mortality in the world. However, clinical progress in the treatment of HCC has not shown a satisfactory therapeutic effect. Here, we have developed a novel strategy to treat HCC with an adenovirus (Ad)-based vaccine, which contains a specific antigen glypican-3 (GPC3) and an immunostimulatory cytokine IL-12. In the subcutaneous tumor model, Ad-IL-12/GPC3 vaccine was injected into muscles three times to evaluate its therapeutic effect. Compared with the control immunization group, the Ad-IL-12/GPC3 immunization group showed a significant tumor growth inhibition effect, which was confirmed by the reduced tumor volume and the increased tumor inhibition. Ad-IL-12/GPC3 co-immunization promoted the induction and maturation of CD11c(+) or CD8(+)CD11c(+) DCs and increased the number of tumor-infiltrating CD8(+) T cells. Furthermore, in the Ad-IL-12/GPC3 group, the proliferation of CD8(+) T cells, the induction of multifunctional CD8(+) T cells, and CTL activity were significantly increased. Interestingly, the deletion of CD8(+) T cells abolished tumor growth inhibition by Ad-IL-12/GPC3 treatment, suggesting that CD8(+) T cell immune responses were required to eliminate the tumor. Likewise, Ad-IL-12/GPC3 vaccine also effectively inhibited lung tumor growth or metastasis by enhancing CD8(+) DCs-mediated multifunctional CD8(+) T cell immune responses in the lung metastasis model. Therefore, these results indicate that IL-12 combined with Ad-GPC3 vaccine co-immunization might provide a promising therapeutic strategy for HCC patients.