Koido Shigeo, Hara Eiichi, Homma Sadamu, Mitsunaga Makoto, Takahara Akitaka, Nagasaki Eijiro, Kawahara Hidejiro, Watanabe Michiaki, Toyama Yoichi, Yanagisawa Satoru, Kobayashi Susumu, Yanaga Katsuhiko, Fujise Kiyotaka, Gong Jianlin, Tajiri Hisao
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan.
J Immunol. 2007 Oct 1;179(7):4874-83. doi: 10.4049/jimmunol.179.7.4874.
Dendritic cell (DC)/tumor cell fusion cells (FCs) can induce potent CTL responses. The therapeutic efficacy of a vaccine requires the improved immunogenicity of both DCs and tumor cells. The DCs stimulated with the TLR agonist penicillin-killed Streptococcus pyogenes (OK-432; OK-DCs) showed higher expression levels of MHC class I and II, CD80, CD86, CD83, IL-12, and heat shock proteins (HSPs) than did immature DCs. Moreover, heat-treated autologous tumor cells displayed a characteristic phenotype with increased expression of HSPs, carcinoembryonic Ag (CEA), MUC1, and MHC class I (HLA-A2 and/or A24). In this study, we have created four types of FC preparation by alternating fusion cell partners: 1) immature DCs fused with unheated tumor cells; 2) immature DCs fused with heat-treated tumor cells; 3) OK-DCs fused with unheated tumor cells; and 4) OK-DCs fused with heat-treated tumor cells. Although OK-DCs fused with unheated tumor cells efficiently enhanced CTL induction, OK-DCs fused with heat-treated tumor cells were most active, as demonstrated by: 1) up-regulation of multiple HSPs, MHC class I and II, CEA, CD80, CD86, CD83, and IL-12; 2) activation of CD4+ and CD8+ T cells able to produce IFN- gamma at higher levels; 3) efficient induction of CTL activity specific for CEA or MUC1 or both against autologous tumor; and 4) superior abilities to induce CD107+ IFN-gamma+ CD8+ T cells and CD154+ IFN-gamma+ CD4+ T cells. These results strongly suggest that synergism between OK-DCs and heat-treated tumor cells enhances the immunogenicity of FCs and provides a promising means of inducing therapeutic antitumor immunity.
树突状细胞（DC）/肿瘤细胞融合细胞（FC）可诱导强烈的细胞毒性T淋巴细胞（CTL）反应。疫苗的治疗效果需要提高DC和肿瘤细胞的免疫原性。用Toll样受体（TLR）激动剂青霉素杀死的化脓性链球菌（OK-432；OK-DC）刺激的DC比未成熟DC表现出更高水平的MHCⅠ类和Ⅱ类分子、CD80、CD86、CD83、白细胞介素-12（IL-12）和热休克蛋白（HSP）。此外，经热处理的自体肿瘤细胞表现出一种特征性表型，其HSP、癌胚抗原（CEA）、黏蛋白1（MUC1）和MHCⅠ类分子（HLA-A2和/或A24）表达增加。在本研究中，我们通过交替融合细胞伙伴创建了四种类型的FC制剂：1）未成熟DC与未加热的肿瘤细胞融合；2）未成熟DC与经热处理的肿瘤细胞融合；3）OK-DC与未加热的肿瘤细胞融合；4）OK-DC与经热处理的肿瘤细胞融合。虽然OK-DC与未加热的肿瘤细胞融合能有效增强CTL诱导，但OK-DC与经热处理的肿瘤细胞融合最为活跃，表现为：1）多种HSP、MHCⅠ类和Ⅱ类分子、CEA、CD80、CD86、CD83和IL-12上调；2）激活能够产生更高水平γ干扰素的CD4⁺和CD8⁺T细胞；（3）有效诱导针对CEA或MUC1或两者的CTL活性，以对抗自体肿瘤；4）诱导CD107⁺γ干扰素⁺CD8⁺T细胞和CD154⁺γ干扰素⁺CD4⁺T细胞的能力更强。这些结果强烈表明，OK-DC与经热处理的肿瘤细胞之间的协同作用增强了FC的免疫原性，并提供了一种诱导治疗性抗肿瘤免疫的有前景的方法。
