OncoTargets and Therapy (Sep 2019)
Intratumoral IL-12 Gene Therapy Inhibits Tumor Growth In A HCC-Hu-PBL-NOD/SCID Murine Model
Abstract
Zhi-Feng Zhou,1,2,* Feng Peng,3,* Jie-Yu Li,1,2 Yun-Bin Ye1,2 1Laboratory of Immuno-Oncology, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fuzhou 350014, People’s Republic of China; 2Fujian Key Laboratory of Translational Cancer Medicine, Fujian Cancer Hospital, Fuzhou 350014, People’s Republic of China; 3Laboratory of Immuno-Oncology, Fujian Medical University Cancer Hospital, Fuzhou 350014, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yun-Bin YeLaboratory of Immuno-Oncology, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, No. 420 Fuma Road, Fuzhou, Fujian Province 350014, People’s Republic of ChinaTel/Fax +86-591-83660063Email [email protected]: This study aimed to evaluate the efficacy and safety of intratumoral IL-12 gene therapy in an HCC-hu-PBL-NOD/SCID mouse model.Materials and methods: The HCC murine model was generated in NOD/SCID mice, and mice with grafted tumors were injected intraperitoneally with 2 × 107 human peripheral blood lymphocytes 14 days after modeling. After 4 days, mice were randomly divided into the 9597/IL-12 group, the 9597/plasmid group and the PBS group. The changes of tumor volume were measured and mouse peripheral blood was sampled post-treatment for ELISA and CBA analyses, and the grafted tumors were collected 28 days post-treatment for immunohistochemistry, ELISA, CBA and detection of cell cycle and apoptosis.Results: The tumor volume was smaller in the 9597/IL-12 group than in the 9597/plasmid and PBS groups on days 7, 14, 21, and 28 post-treatment (P < 0.05). Higher IL-12 levels were detected in the peripheral blood and the supernatants of grafted tumor homogenates in the 9597/IL-12 group than in the 9597/plasmid and PBS groups 7, 14, 21 and 28 days post-treatment (P < 0.05). IHC revealed higher counts of CD3+T cells, CD4+T helper cells, IFN-γ Th1 cells+ and S-100 protein positive dentric cells and lower MVD in the 9597/IL-12 group than in the 9597/plasmid and PBS groups (P < 0.05). Flow cytometry showed a significantly higher proportion of HCC cells at the G0/G1 phase and a significantly lower proportion of HCC cells at the S phase in the 9597/IL-12 group than in the PBS group (P < 0.05) and a greater apoptotic rate of HCC cells in the 9597/IL-12 group than in the 9597/plasmid and PBS groups (P < 0.05).Conclusion: Intratumoral IL-12 gene therapy may inhibit tumorigenesis with mild adverse effects in a HCC-hu-PBL-NOD/SCID murine model through inhibiting angiogenesis, arresting cells in G0/G1 phase and inducing apoptosis.Keywords: hepatocellular carcinoma, IL-12, gene therapy, efficacy, toxicity
