同時轉染IL-6轉殖基因可提升樹突狀細胞與分泌TGF-β1細胞融合疫苗的免疫力

Abstract

在近年來，樹突細胞相關的抗癌疫苗(Dendritic cell (DC)-based antitumor vaccine)被視為很具發展潛力的癌症免疫治療方式。然而，在臨床的實行上只有某部分的病人在經過樹突細胞疫苗治療後有出現明顯腫瘤消退的現象。其中一個可能的解釋是很多惡性腫瘤可能會透過分泌免疫抑制的因子，像TGF-β1，的方式透過抑制宿主的免疫反應來限制樹突細胞疫苗的效力。在此研究中，我們展現了同時地將免疫調節相關的基因傳遞進細胞中並融合細胞可以提升樹突細胞融合疫苗的效力。 在本研究中，IL-6 因為具有拮抗TGF-β1 的免疫抑制活性的能力，被拿來作為實驗中的轉殖基因。此外，LPPC (Lipo-PEI-PEG Complex)，我們實驗室所開發的創新帶正電微脂體，在同時融合與轉染的過程中扮演轉染劑的角色。結果顯示，LPPC 的加入不會影響PEG 的融合效率而且同時地IL-6 轉殖基因也成功地被LPPC 帶入細胞。一致地，接種LPPC/IL-6/PEG 樹突細胞融合疫苗的動物引發出較佳的免疫反應。因此，我們認為此製作疫苗的策略具有在臨床應用上提升基因改良的樹突細胞融合疫苗的應用潛能。

Dendritic cell (DC)-based antitumor vaccine is a promising immunotherapy for cancer in recent years. However, the clinical results in the clinical trails showed that the treatments of DC vaccines benefit only a subset of patients to result in tumor regression. One possible explanation has been suggested that many malignant tumors would secrete immunosuppressive factors such as TGF-β1, which is possible to limit the efficacy of the DC-based vaccine by suppressing the host immune responses. In this study, we demonstrated that delivering an immuno-modulated gene into cells and fusing cells simultaneously could improve the efficacy of DC fusion vaccine. IL-6, an antagonist against the immunosuppressive activity of TGF-β1, was used as the transgene in this study. In addition, LPPC, a novel cationic liposome, plays the role in the co-transfection during fusion process. The results showed that the addition of LPPC didn’t interfere with the fusion efficiency of PEG and it indeed transfected simultaneously the IL-6 gene into the cells during the fusion process. Consistently, animals vaccinated with LPPC/IL-6/PEG DC vaccines elicit superior immunogenic effects. Therefore, this strategy may have the potential to be a promising strategy for gene-modified DC fusion vaccine in the clinical use.