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病人来源的胶质瘤干细胞被特异性CD133-CAR-T细胞杀死但会诱导T细胞表达老化标志物CD57

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发表于 2015-11-18 22:25:45 | 显示全部楼层 |阅读模式
Patient-derived glioblastoma stem cells are killed by CD133-specific CAR T cells but induce the T cell aging marker CD57
病人来源的胶质瘤干细胞被特异性CD133-CAR-T细胞杀死但会诱导T细胞表达老化标志物CD57
摘要:
CD133 的抗原决定簇AC133是许多实体肿瘤的癌症干细胞(CSC的标记物,包括了高度恶性多形性胶质母细胞瘤(GBM。我们已经开发了一个AC133特异性嵌合抗原受体(CAR)表明在体外和原位肿瘤模型的体内,AC133-CAR-T细胞能杀死AC133+ GBM干细胞(GBM-SCs)。与来自患者的GBM细胞直接接触导致CAR-T细胞表面CD57迅速上调,一个已知的用来标记分化终端或接近分化终端T细胞的分子。然而,其他与终端T细胞分化相关的变化不容易被检测到。CD57在神经嵴起源的肿瘤细胞表面表达,也已经优先在高活性、未分化的多潜能肿瘤干细胞上发现。我们发现,只在接触过CD57阳性、病人来源的GBM干细胞后,CD57在活化的T细胞表面表达才会上调,不会因接触传统的CD57-阴性的胶质瘤系表达上调。然而,CD57不会随着GBM-SCs的分化而表达下调,这说明这个分子不是GBM的忠实癌症干细胞标记物。分化的GBM细胞仍然会诱导CAR-T细胞和其他活性T细胞表达CD57。因此,通过接触CD57阳性靶细胞,在活化的人类T细胞表面,CD57会明显的上调。
关键词:嵌合抗原受体,肿瘤干细胞,胶质瘤,免疫治疗,肿瘤
Abstract
The AC133 epitope of CD133 is a cancer stem cell (CSC) marker for many tumor entities, including the highly malignant glioblastoma multiforme (GBM). We have developed an AC133-specific chimeric antigen receptor (CAR) and show that AC133-CAR T cells kill AC133+ GBM stem cells (GBM-SCs) both in vitro and in an orthotopic tumor model in vivo. Direct contact with patient-derived GBM-SCs caused rapid upregulation of CD57 on the CAR T cells, a molecule known to mark terminally or near-terminally differentiated T cells. However, other changes associated with terminal T cell differentiation could not be readily detected. CD57 is also expressed on tumor cells of neural crest origin and has been preferentially found on highly aggressive, undifferentiated, multipotent CSC-like cells. We found that CD57 was upregulated on activated T cells only upon contact with CD57+ patient-derived GBM-SCs, but not with conventional CD57-negative glioma lines. However, CD57 was not downregulated on the GBM-SCs upon their differentiation, indicating that this molecule is not a bona fide CSC marker for GBM. Differentiated GBM cells still induced CD57 on CAR T cells and other activated T cells. Therefore, CD57 can apparently be upregulated on activated human T cells by mere contact with CD57+ target cells.
Keywords: chimeric antigen receptor, cancer stem cell, glioblastoma, immunotherapy, CD57

Patient-derived glioblastoma stem cells are killed by CD133-specific CAR T cells.pdf

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