Therapeutic Efficacy of Delta-Like Ligand 4 Gene Vaccine Overexpression on Liver Cancer in Mice

Abstract

Delta-like ligand 4 is a notch ligand that is predominantly expressed in the endothelial tip cells and plays essential roles in the regulation of angiogenesis. In this study, we explored the therapeutic effects of delta-like ligand 4 gene vaccine overexpression on the syngeneic model mouse model of liver cancer and the underlying mechanisms. Mouse hepatocellular carcinoma cell line H22-H8D8 was used to generate subcutaneous syngeneic model liver cancer in Kunming mice, and the effects of recombinant plasmid pVAX1 containing delta-like ligand 4 vaccine on tumor growth was examined. Compared to controls, delta-like ligand 4 vaccination reduced syngeneic model tumor size by 70.31% (from 17.11 ± 9.30 cm3 to 5.08 ± 2.75 cm3, P = .035) and tumor weight by 34.19% (from 6.26 ± 3.01 g to 4.12 ± 2.52 g, P = .102), while the mouse survival was significantly increased (from 27.7 ± 6.0 days to 33.1 ± 6.1 days, P = .047). High level of delta-like ligand 4 antibody, together with a significantly increased number of CD4+ and decreased CD8+ cells were identified in the mouse peripheral blood serum samples after delta-like ligand 4 immunization. In addition, elevated serum levels of interleukin 2, interleukin 4, and interferon γ were detected in the delta-like ligand 4–vaccinated mice when compared to the controls. Further studies have revealed increased CD31 and decreased Ki67 expression in the syngeneic model tumor tissues of vaccinated mice. Taken together, our studies suggest that delta-like ligand 4 gene vaccine can inhibit the growth of hepatocellular carcinoma in mice through inhibiting tumor angiogenesis and boosting antitumor immune responses. Hence, delta-like ligand 4 gene vaccination may be a promising strategy for the treatment of transplanted liver cancer.