Zhu Xuekai, Prasad Shruthi, Gaedicke Simone, Hettich Michael, Firat Elke, Niedermann Gabriele
Department of Radiation Oncology, University Hospital Freiburg, Freiburg, Germany.
Department of Radiation Oncology, University Hospital Freiburg, Freiburg, Germany. Faculty of Biology, University of Freiburg, Freiburg, Germany.
Oncotarget. 2015 Jan 1;6(1):171-84. doi: 10.18632/oncotarget.2767.
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.
CD133的AC133表位是许多肿瘤实体的癌症干细胞（CSC）标志物，包括高度恶性的多形性胶质母细胞瘤（GBM）。我们开发了一种AC133特异性嵌合抗原受体（CAR），并表明AC133-CAR T细胞在体外和体内原位肿瘤模型中均可杀死AC133 + GBM干细胞（GBM-SCs）。与患者来源的GBM-SCs直接接触导致CAR T细胞上CD57迅速上调，CD57是一种已知可标记终末或接近终末分化T细胞的分子。然而，与终末T细胞分化相关的其他变化不易检测到。CD57也在神经嵴来源的肿瘤细胞上表达，并且优先在高度侵袭性、未分化、多能的CSC样细胞上发现。我们发现，仅在与CD57 +患者来源的GBM-SCs接触时，活化T细胞上的CD57才会上调，而与传统的CD57阴性胶质瘤细胞系接触时则不会。然而，GBM-SCs分化后CD57并未下调，这表明该分子不是GBM真正的CSC标志物。分化的GBM细胞仍可诱导CAR T细胞和其他活化T细胞上的CD57上调。因此，仅通过与CD57 +靶细胞接触，活化的人T细胞上的CD57显然就可以上调。
