Matsuyoshi Hidetake, Hirata Shinya, Yoshitake Yoshihiro, Motomura Yutaka, Fukuma Daiki, Kurisaki Akari, Nakatsura Tetsuya, Nishimura Yasuharu, Senju Satoru
Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
Cancer Sci. 2005 Dec;96(12):889-96. doi: 10.1111/j.1349-7006.2005.00123.x.
The close cooperation of both innate and acquired immunity is essential for the induction of truly effective antitumor immunity. We tested a strategy to enhance the cross-talk between NKT cells and conventional antigen-specific T cells with the use of alpha GalCer-loaded dendritic cells genetically engineered to express antigen plus chemokine, attracting both conventional T cells and NKT cells. DC genetically engineered to express a model antigen, OVA, along with SLC/CCL21 or monokine induced by IFN-gamma/CXCL9, had been generated using a method based on in vitro differentiation of DC from mouse ES cells. The ES-DC were loaded with alpha-GalCer and transferred to mice bearing MO4, an OVA-expressing melanoma, and their capacity to evoke antitumor immunity was evaluated. In vivo transfer of either OVA-expressing ES-DC, stimulating OVA-reactive T cells, or alpha-GalCer-loaded non-transfectant ES-DC, stimulating NKT cells, elicited a significant but limited degree of protection against the i.p. disseminated MO4. A more potent antitumor effect was observed when alpha-GalCer was loaded to ES-DC expressing OVA before in vivo transfer, and the effect was abrogated by the administration of anti-CD8, anti-NK1.1 or anti-asialo GM1 antibody. alpha-GalCer-loaded double transfectant ES-DC expressing SLC along with OVA induced the most potent antitumor immunity. Thus, alpha-GalCer-loaded ES-DC expressing tumor-associated antigen along with SLC can stimulate multiple subsets of effector cells to induce a potent therapeutic effect against peritoneally disseminated tumor cells. The present study suggests a novel way to use alpha-GalCer in immunotherapy for peritoneally
先天性免疫和获得性免疫的密切合作对于诱导真正有效的抗肿瘤免疫至关重要。我们测试了一种策略，即利用基因工程改造的负载α-半乳糖神经酰胺（α GalCer）的树突状细胞来增强自然杀伤T细胞（NKT细胞）与传统抗原特异性T细胞之间的相互作用，该树突状细胞经基因工程改造后可表达抗原及趋化因子，吸引传统T细胞和NKT细胞。利用基于从小鼠胚胎干细胞体外分化树突状细胞的方法，已构建出经基因工程改造后表达模型抗原卵清蛋白（OVA）以及二级淋巴组织趋化因子（SLC/CCL21）或γ干扰素诱导的单核因子（MIG/CXCL9）的树突状细胞。将这些胚胎干细胞来源的树突状细胞（ES-DC）负载α-GalCer后，转移至携带表达OVA的黑色素瘤MO4的小鼠体内，并评估其激发抗肿瘤免疫的能力。体内转移表达OVA的ES-DC（刺激OVA反应性T细胞）或负载α-GalCer的未转染ES-DC（刺激NKT细胞），均可对腹腔播散的MO4产生显著但有限程度的保护作用。在体内转移前将α-GalCer负载至表达OVA的ES-DC时，观察到更强的抗肿瘤效果，且该效果可被抗CD8、抗NK1.1或抗去唾液酸GM1抗体消除。负载α-GalCer的双转染ES-DC同时表达SLC和OVA可诱导最强的抗肿瘤免疫。因此，负载α-GalCer且表达肿瘤相关抗原及SLC的ES-DC可刺激多个效应细胞亚群，从而对腹腔播散的肿瘤细胞产生强大的治疗效果。本研究提示了一种在腹膜免疫治疗中使用α-GalCer的新方法。
