Therapy of Peritoneally Disseminated Colon Cancer by TAP-Deficient Embryonic Stem Cell-Derived Macrophages in Allogeneic Recipients
Therapy of Peritoneally Disseminated Colon Cancer by TAP-Deficient Embryonic Stem Cell-Derived Macrophages in Allogeneic Recipients
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DOI：
10.4049/jimmunol.1303473
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发表时间：
2014-08-15
影响因子：
4.4
通讯作者：
Senju, Satoru
中科院分区：
文献类型：
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作者：
Haga, Eriko;Endo, Yuko;Senju, Satoru
我们建立了一种从小鼠胚胎干细胞(ES)中产生大量髓系细胞的方法，称为ES细胞来源的增殖性髓系细胞系(ES-ML)。ES-ML在M-CSF和GM-CSF存在下持续增殖。ES-ML基因修饰表达抗HER2(Neu)mAb单链V区片段，减少了共培养的表达HER2的小鼠结肠癌细胞的数量。用干扰素-γ和脂多糖或肿瘤坏死因子刺激ES-ML后，ES-ML几乎完全杀伤结肠-26细胞，其杀伤作用部分是由ES-ML产生的NO介导的。将ES-ML注射到腹腔注射的小鼠体内。建立了结肠-26肿瘤，它们有效地渗透到肿瘤组织中。注射重组干扰素-γ和脂多糖的ES-ML可抑制小鼠腹膜癌的发展。肿瘤坏死因子转基因或未转基因的ES-ML与重组干扰素-γ共注射可抑制肿瘤生长并延长治疗组小鼠的存活时间。在本实验中，与抗原加工相关的转运蛋白(TAP)1缺陷的ES-ML在MHC不匹配的同种异基因受体小鼠中显示出治疗活性。尽管ES-ML具有增殖能力，但在受体小鼠中，转移的ES-ML从未发展为恶性肿瘤。总之，具有抗癌特性的TAP缺陷ES-ML在异基因受者中显示出治疗效果，提示TAP缺陷的人诱导多能干细胞来源的增殖性髓系可能用于癌症治疗。
We established a method to generate a large quantity of myeloid lineage cells from mouse embryonic stem (ES) cells, termed ES cell-derived proliferating myeloid cell lines (ES-ML). ES-ML continuously proliferated in the presence of M-CSF and GM-CSF. ES-ML genetically modified to express an anti-HER2 (neu) mAb single-chain V region fragment reduced the number of cocultured mouse Colon-26 cancer cells expressing HER2. Stimulation of ES-ML with IFN-gamma plus LPS or TNF resulted in almost complete killing of the Colon-26 cells by the ES-ML, and the cytotoxicity was mediated, in part, by NO produced by ES-ML. When ES-ML were injected into mice with i.p. established Colon-26 tumors, they efficiently infiltrated the tumor tissues. Injection of ES-ML with rIFN-gamma and LPS inhibited cancer progression in the mouse peritoneal cavity. Coinjection of TNF-transfected or untransfected ES-ML with rIFN-gamma inhibited cancer growth and resulted in prolonged survival of the treated mice. In this experiment, transporter associated with Ag processing (TAP) 1-deficient ES-ML exhibited therapeutic activity in MHC-mismatched allogeneic recipient mice. Despite the proliferative capacity of ES-ML, malignancy never developed from the transferred ES-ML in the recipient mice. In summary, TAP-deficient ES-ML with anticancer properties exhibited a therapeutic effect in allogeneic recipients, suggesting the possible use of TAP-deficient human-induced pluripotent stem cell-derived proliferating myeloid cell lines in cancer therapy.