Nakahara Norimoto, Pollack Ian F, Storkus Walter J, Wakabayashi Toshihiko, Yoshida Jun, Okada Hideho
Department of Bio-Medicine, Nagoya University School of Medicine, Nagoya, Japan.
Cancer Gene Ther. 2003 Jul;10(7):549-58. doi: 10.1038/sj.cgt.7700598.
As type I interferons (IFNs) enhance the stimulatory activity of dendritic cells (DCs), we hypothesized that transfection of glioma cells with the IFN-beta gene in the presence of DCs would provide particularly effective antitumor activity by both facilitating apoptosis of glioma cells and presenting the resulting glioma antigens to T cell by DCs, thereby inducing specific T-cell responses against glioma cells. A mouse glioma cell line 203G was first transfected with cDNA encoding IFN-beta using cationic liposomes, then cocultured with syngeneic bone marrow-derived DCs and naïve splenic T cells. The 203G cells were almost completely killed following 96-hour coculture with DCs and T cells, and strong tumor-specific cytotoxic T-lymphocyte (CTL) activity accompanied by high level interleukin (IL)-12 and IFN-gamma production was observed in culture. In addition, omission of either IFN-beta gene delivery, DCs or T cells from the coculture completely abrogated the induction of the CTL activity, suggesting that the combination of these components was required to elicit an optimal effect. On the basis of these in vitro data, syngeneic animals bearing subcutaneous 203G tumors received intratumoral injections of IFN-beta gene and DCs. Suppression of the tumor growth by this combinational therapy was superior to treatment with DC or IFN-beta gene solely. This combination may constitute a new therapeutic strategy to induce potent antiglioma immune responses.
由于I型干扰素（IFN）可增强树突状细胞（DC）的刺激活性，我们推测，在DC存在的情况下，用IFN-β基因转染胶质瘤细胞，通过促进胶质瘤细胞凋亡以及由DC将产生的胶质瘤抗原呈递给T细胞，从而诱导针对胶质瘤细胞的特异性T细胞反应，将产生特别有效的抗肿瘤活性。首先使用阳离子脂质体将编码IFN-β的cDNA转染小鼠胶质瘤细胞系203G，然后与同基因骨髓来源的DC和未致敏的脾T细胞共培养。与DC和T细胞共培养96小时后，203G细胞几乎被完全杀死，并且在培养物中观察到强烈的肿瘤特异性细胞毒性T淋巴细胞（CTL）活性，同时伴有高水平的白细胞介素（IL）-12和IFN-γ产生。此外，在共培养中省略IFN-β基因传递、DC或T细胞中的任何一种，都完全消除了CTL活性的诱导，这表明需要这些成分的组合才能产生最佳效果。基于这些体外数据，携带皮下203G肿瘤的同基因动物接受瘤内注射IFN-β基因和DC。这种联合治疗对肿瘤生长的抑制作用优于单独使用DC或IFN-β基因治疗。这种联合可能构成一种诱导有效抗胶质瘤免疫反应的新治疗策略。
