Division of Gene Therapy Science, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan.
Department of Device Application for Molecular Therapeutics, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan.
Cancer Gene Ther. 2020 Jun;27(6):498-508. doi: 10.1038/s41417-019-0126-6. Epub 2019 Aug 6.
Inactivated Sendai virus particle (or hemagglutinating virus of Japan envelope; HVJ-E) has been previously reported to possess antitumour properties that activate antitumour immunity. Two glycoproteins, fusion (F) and hemagglutinin-neuraminidase (HN), are present on the surface of HVJ-E. HN is necessary for binding to receptors such as acidic gangliosides, and F induces membrane fusion by associating with membrane lipids. We previously reported that liposomes reconstituted with F but not HN showed antitumour activity by inducing IL-6 secretion in dendritic cells (DCs), suggesting that F protein is capable of eliciting antitumour activity. Here, we attempted to deliver F gene into tumour tissue in mice by electroporation and demonstrated that F gene therapy retarded tumour growth, increased CD4 and CD8 T-cell infiltration into tumours and induced tumour-specific IFN-γ T-cell response. However, neutralisation of IL-6R signalling did not impact F plasmid-mediated antitumour effect. Instead, we found that F plasmid treatment resulted in a significant increase in the secretion of the chemokine RANTES (regulated upon activation, normal T cell expressed and secreted) by tumour-infiltrating T cells. Neutralising antibody against RANTES abolished the antitumour effect of F plasmid treatment in a dose-dependent manner. Thus, F gene therapy may show promise as a novel therapeutic for single or combined cancer immunotherapy.
已报道，灭活的仙台病毒粒子（或血凝性日本病毒包膜；HVJ-E）具有激活抗肿瘤免疫的抗肿瘤特性。HVJ-E 表面存在两种糖蛋白，融合（F）和血凝素神经氨酸酶（HN）。HN 对于与酸性神经节苷脂等受体结合是必需的，而 F 通过与膜脂质结合诱导膜融合。我们之前报道，用 F 但不用 HN 重建的脂质体通过诱导树突状细胞（DC）分泌 IL-6 显示出抗肿瘤活性，表明 F 蛋白能够引发抗肿瘤活性。在这里，我们通过电穿孔尝试将 F 基因递送到小鼠的肿瘤组织中，并证明 F 基因治疗可延缓肿瘤生长、增加 CD4 和 CD8 T 细胞浸润肿瘤并诱导肿瘤特异性 IFN-γ T 细胞反应。然而，中和 IL-6R 信号传导并没有影响 F 质粒介导的抗肿瘤作用。相反，我们发现 F 质粒处理导致肿瘤浸润 T 细胞中趋化因子 RANTES（活化调节正常 T 细胞表达和分泌）的分泌显著增加。针对 RANTES 的中和抗体以剂量依赖性方式消除了 F 质粒处理的抗肿瘤作用。因此，F 基因治疗可能是一种有前途的单一或联合癌症免疫治疗的新疗法。
