Recognition and killing of brain tumor stem-like initiating cells by CD8+ cytolytic T cells.
Recognition and killing of brain tumor stem-like initiating cells by CD8+ cytolytic T cells.
复制标题
DOI：
10.1158/0008-5472.can-09-2687
复制
发表时间：
2009-12-01
期刊：
影响因子：
11.2
通讯作者：
Jensen MC
中科院分区：
文献类型：
--
作者：
Brown CE;Starr R;Martinez C;Aguilar B;D'Apuzzo M;Todorov I;Shih CC;Badie B;Hudecek M;Riddell SR;Jensen MC
实体瘤含有干细胞亚群，可抵抗化疗/放射治疗的细胞毒作用，但其对细胞溶解T淋巴细胞(CTL)效应机制的敏感性尚未得到很好的表征。使用一组来自高级别胶质瘤的早期传代的人脑肿瘤干细胞(BTSC)，我们证明BTSC受到CD8+CTL的免疫识别和消除。与血清分化的低CD133肿瘤细胞和已建立的胶质瘤细胞系相比，BTSCs在HLA-I和ICAM-1的表达水平方面是相同的，在触发脱颗粒和由抗原特异性CTL合成细胞因子的能力方面相似，并且对穿孔素依赖的CTL介导的细胞溶解同样敏感。BTSC还具有处理和提呈抗原的能力，当抗原内源性表达时，CTL对这些细胞的杀伤就证明了这一点。此外，我们发现CTL可以在体内以抗原特异性的方式消除所有具有肿瘤启动活性的BTSCs。目前的模型预测，许多癌症的根治疗法将需要消除干细胞/起始群体，这些研究为开发免疫治疗方法以根除这一肿瘤群体奠定了基础。
Solid tumors contain a subset of stem-like cells that are resistant to the cytotoxic effects of chemo/radio-therapy, but their susceptibility to cytolytic T lymphocyte (CTL) effector mechanisms has not been well characterized. Using a panel of early-passage human brain tumor stem cell (BTSC) lines derived from high-grade gliomas, we demonstrate that BTSCs are subject to immunologic recognition and elimination by CD8+ CTLs. Compared to serum differentiated CD133low tumor cells and established glioma cell lines, BTSCs are equivalent with respect to expression levels of HLA class I and ICAM-1, similar in their ability to trigger degranulation and cytokine synthesis by antigen-specific CTLs, and equally susceptible to perforin-dependent CTL mediated cytolysis. BTSCs are also competent in the processing and presentation of antigens as evidenced by the killing of these cells by CTL when antigen is endogenously expressed. Moreover, we show that CTLs can eliminate all BTSCs with tumor initiating activity in an antigen specific manner in vivo. Current models predict that curative therapies for many cancers will require the elimination of the stem/initiating population, and these studies lay the foundation for developing immunotherapeutic approaches to eradicate this tumor population.