Intratumoral Neoadjuvant Immunotherapy Using IL-12 and Dendritic Cells Is an Effective Strategy To Control Recurrence of Murine Hepatocellular Carcinoma in Immunosuppressed Mice

摘要

Liver transplantation is accepted as an effective therapy for hepatocellular carcinoma (HCC). However, recurrence is one of the most fatal complications. The aim of this study is to evaluate the efficacy of intratumoral immunotherapy using IL-12 gene therapy and dendritic cell injection for the purpose of effective treatment for HCC under conditions of immunosuppression. We found that the combined immunotherapy significantly induced sustained and high amounts of intratumoral IL-12 and IFN-γ proteins and that it induced high HCC-specific CTL activity under immunosuppression as compared with each monotherapy or control. The combined immunotherapy also exerted effective antitumor effects on the immunosuppressed host, resulting in significant suppression of growth of the s.c. established tumor and complete suppression of lung and liver metastasis, without rejection of a fully allogeneic skin graft. These antitumor effects were dependent on both T cells and NK cells. Noteworthily, the combined intratumoral immunotherapy and tumor resection (that is, neoadjuvant immunotherapy) resulted in achievement of tumor-free and long-term survival of the some immunosuppressed mice, even when the mice were challenged with i.v. injection of HCC at the time of tumor resection. In contrast, all of the mice treated with neoadjuvant immunotherapy using monotherapy or control therapy suffered from lung and liver metastasis. These results suggest that intratumoral neoadjuvant immunotherapy using IL-12 gene therapy and dendritic cell therapy is a potent effective strategy to control recurrence of HCC in patients after liver transplantation for HCC and may be applicable to general cancer treatment.