Combined interleukin-12 and Dendritic cell neoadjuvant immunotherapy for hepatocellular carcinoma in immunosuppressed mice

肝移植治疗肝细胞癌时，复发的肝细胞癌是最致命的并发症之一。其中一个原因是免疫抑制剂导致的免疫力下降。本研究旨在评价免疫抑制状态下白细胞介素12(IL-12)联合树突状细胞(DC)新辅助免疫治疗肝癌的疗效。将MH134细胞(H-2k)接种于C3H小鼠(H-2k)，采用肿瘤内电穿孔介导的小鼠IL-12(mIL-12)联合骨髓来源的DC免疫疗法治疗已建立的肝癌模型。治疗7天后开始注射FK506，进入免疫控制状态。我们的结果表明，mIL-12和DC联合治疗可在肿瘤内产生大量的mIL-12和干扰素-γ，并显示出比单独mIL-12和DC治疗更强的MH134特异性细胞杀伤活性。联合应用mIL-12和DC可显著抑制S的生长。与mIL-12单独治疗和DC单独治疗相比，c.建立了mIL-12载体和DC联合注射的肝癌模型，并减少了自发的肺和肝转移。特别值得一提的是，mIL-12和DC联合治疗没有发现任何自发的肺和肝转移。这些结果提示，联合应用IL-12和DC新辅助免疫治疗是预防免疫抑制患者肝移植后肝细胞癌复发的有效策略。

When liver transplantation is performed as a therapy for hepatocellular carcinoma (HCC), recurrent HCC is one of the most fatal complications. One of the reasons is the decrease of immunity by immunosuppressed agents. The aim of this study is to evaluate the efficacy of combined interleukin-12 (IL-12) and dendritic cell (DC) neoadjuvant immunotherapy for HCC under immunosuppression. C3H mice (H-2k) were s. c. implanted with MH134 cells (H-2k) and we treated the established HCC with combined intratumoral electroporation-mediated murine IL-12 (mIL-12) and bone marrow derived DC-based immunotherapy. 7 days after this therapy, we started the FK506 i. p. injection to put into the state of the immunity control. Our results demonstrated combined therapy with mIL-12 and DC produced highly amounts of intratumoral mIL-12 and IFN-γ and showed stronger MH134-specific cytolytic activity more than mIL-12 therapy alone and DC therapy alone. Combined therapy with mIL-12 and DC induced a significant suppression of the growth of s. c. established HCC into which the mIL-12 vector and DC had been directory injected compared to mIL-12 therapy alone and DC therapy alone, as well as reduced both spontaneous lung and liver metastases. In particularly, combined therapy with mIL-12 and DC did not show any spontaneous lung and liver metastases. These results suggest combined IL-12 and DC neoadjuvant immunotherapy is a potent effective strategy to prevent recurrences of HCC in immunosupressed patients undergone liver transplantation.