Embryonic stem cell-derived dendritic cells expressing glypican-3, a recently identified oncofetal antigen, induce protective immunity against highly metastatic mouse melanoma, B16-F10
Embryonic stem cell-derived dendritic cells expressing glypican-3, a recently identified oncofetal antigen, induce protective immunity against highly metastatic mouse melanoma, B16-F10
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DOI：
10.1158/0008-5472.can-05-2090
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发表时间：
2006-02-15
期刊：
影响因子：
11.2
通讯作者：
Nishimura, Y
中科院分区：
文献类型：
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作者：
Motomura, Y;Senju, S;Nishimura, Y
我们最近建立了一种从小鼠胚胎干细胞产生树突状细胞的方法。通过将外源基因导入胚胎干细胞并随后诱导分化为树突状细胞（ES-DC），我们现在可以容易地产生表达转基因的转染子ES-DC。先前的研究表明，表达模型抗原卵清蛋白的遗传修饰的ES-DC的转移保护了受体小鼠免受表达卵清蛋白的肿瘤的攻击。在本研究中，我们研究了表达人磷脂酰肌醇蛋白聚糖-3小鼠同源物的ES-DC的能力，这是一种最近发现的在人黑色素瘤和肝细胞癌中表达的癌胚抗原，可以引起对磷脂酰肌醇蛋白聚糖-3表达小鼠肿瘤的保护性免疫。通过磷脂酰肌醇蛋白聚糖-3转染子ES-DC（ES-DC-GPC 3）的体内转移引发对多个磷脂酰肌醇蛋白聚糖-3表位特异性的CTL。ES-DC-GPC 3的转移保护受体小鼠免受随后的B16-F10黑色素瘤（天然表达磷脂酰肌醇蛋白聚糖-3）和磷脂酰肌醇蛋白聚糖-3转染剂MCA 205肉瘤的攻击。用ES-DC-GPC 3的治疗对静脉内注射的B16-F10也高度有效。这些治疗没有观察到有害的副作用，如自身免疫。耗竭实验和免疫组化分析表明，CD 8（+）和CD 4（+）T细胞都有助于观察到的抗肿瘤作用。总之，磷脂酰肌醇蛋白聚糖-3作为抗黑素瘤免疫治疗的靶抗原的有用性因此在使用ES-DC系统的小鼠模型中显示。表达磷脂酰肌醇蛋白聚糖-3的人树突状细胞有望成为黑色素瘤和肝癌的治疗手段。
We have recently established a method to generate dendritic cells from mouse embryonic stem cells. By introducing exogenous genes into embryonic stem cells and subsequently inducing differentiation to dendritic cells (ES-DC), we can now readily generate transfectant ES-DC expressing the transgenes. A previous study revealed that the transfer of genetically modified ES-DC expressing a model antigen, ovalbumin, protected the recipient mice from a challenge with an ovalbumin-expressing tumor. In the present study, we examined the capacity of ES-DC expressing mouse homologue of human glypican-3, a recently identified oncofetal antigen expressed in human melanoma and hepatocellular carcinoma, to elicit protective immunity against glypican-3-expressing mouse tumors. CTLs specific to multiple glypican-3 epitopes were primed by the in vivo transfer of glypican-3-transfectant ES-DC (ES-DC-GPC3). The transfer of ES-DC-GPC3 protected the recipient mice from subsequent challenge with B16-F10 melanoma, naturally expressing glypican-3, and with glypican-3-transfectant MCA205 sarcoma. The treatment with ES-DC-GPC3 was also highly effective against i.v. injected B16-F10. No harmful side effects, such as autoimmunity, were observed for these treatments. The depletion experiments and immunohistochemical analyses suggest that both CD8(+) and CD4(+) T cells contributed to the observed antitumor effect. In conclusion, the usefulness of glypican-3 as a target antigen for antimelanoma immunotherapy was thus shown in the mouse model using the ES-DC system. Human dendritic cells expressing glypican-3 would be a promising means for therapy of melanoma and hepatocellular carcinoma.