Stem-like tumor-initiating cells isolated from IL13Rα2 expressing gliomas are targeted and killed by IL13-zetakine-redirected T Cells.
Stem-like tumor-initiating cells isolated from IL13Rα2 expressing gliomas are targeted and killed by IL13-zetakine-redirected T Cells.
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DOI：
10.1158/1078-0432.ccr-11-1669
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发表时间：
2012-04-15
期刊：
影响因子：
--
通讯作者：
Jensen MC
中科院分区：
文献类型：
--
作者：
Brown CE;Starr R;Aguilar B;Shami AF;Martinez C;D'Apuzzo M;Barish ME;Forman SJ;Jensen MC
评价IL 13 R α2作为消除高级别胶质瘤中胶质瘤干细胞样起始细胞（GSC）的免疫靶点，特别关注基因工程IL 13 R α2特异性原代人CD 8+细胞毒性T淋巴细胞（IL 13-zetakine+ CTL）靶向该治疗耐药胶质瘤亚群的潜力。一组低传代GSC肿瘤球和血清分化的胶质瘤细胞系从患者胶质母细胞瘤标本中扩增。评估了这些胶质母细胞瘤细胞系的IL 13 R α2表达以及对IL 13-zetakine+ CTL介导的体外和体内杀伤的敏感性。我们观察到，虽然胶质瘤IL 13 R α2表达在患者之间存在差异，但对于IL 13 R α 2 pos病例，在GSC和更分化的肿瘤细胞群中均检测到该抗原。IL 13-zetakine+ CTL能够在体外有效识别和杀死IL 13 R α 2 pos GSC和IL 13 R α 2 pos分化的细胞，以及消除原位小鼠肿瘤模型中的胶质瘤起始活性。此外，颅内给予IL 13-zetakine+ CTL对小鼠中已建立的IL 13 R α 2 pos GSC肿瘤球引发的原位肿瘤显示出稳健的抗肿瘤活性。在表达IL 13 R α2的高级别胶质瘤中，该受体由GSC和分化的肿瘤群体表达，使得两者都可被IL 13-zetakine+ CTL靶向。因此，我们的结果支持IL 13 R α2导向的免疫抑制方法用于根除治疗抗性GSC群体的潜在效用。
To evaluate IL13Rα2 as an immunotherapeutic target for eliminating glioma stem-like initiating cells (GSC) of high-grade gliomas, with particular focus on the potential of genetically engineered IL13Rα2-specific primary human CD8+ cytotoxic T lymphocytes (IL13-zetakine+ CTL) to target this therapeutically resistant glioma subpopulation. A panel of low-passage GSC tumor sphere and serum-differentiated glioma lines were expanded from patient glioblastoma specimens. These glioblastoma lines were evaluated for expression of IL13Rα2 and for susceptibility to IL13-zetakine+ CTL-mediated killing in vitro and in vivo. We observed that while glioma IL13Rα2 expression varies between patients, for IL13Rα2pos cases this antigen was detected on both GSCs and more differentiated tumor cell populations. IL13-zetakine+ CTL were capable of efficient recognition and killing of both IL13Rα2pos GSC and IL13Rα2pos differentiated cells in vitro, as well as eliminating glioma initiating activity in an orthotopic mouse tumor model. Furthermore, intracranial administration of IL13-zetakine+ CTL displayed robust anti-tumor activity against established IL13Rα2pos GSC tumor sphere-initiated orthotopic tumors in mice. Within IL13Rα2-expressing high-grade gliomas, this receptor is expressed by GSCs and differentiated tumor populations, rendering both targetable by IL13-zetakine+ CTLs. Thus, our results support the potential utility of IL13Rα2-directed immunotherapeutic approaches for eradicating therapeutically resistant GSC populations.