Recognition and killing of autologous, primary glioblastoma tumor cells by human cytomegalovirus pp65-specific cytotoxic T cells.
Recognition and killing of autologous, primary glioblastoma tumor cells by human cytomegalovirus pp65-specific cytotoxic T cells.
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DOI：
10.1158/1078-0432.ccr-13-3268
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发表时间：
2014-05-15
期刊：
影响因子：
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通讯作者：
Mitchell DA
中科院分区：
文献类型：
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作者：
Nair SK;De Leon G;Boczkowski D;Schmittling R;Xie W;Staats J;Liu R;Johnson LA;Weinhold K;Archer GE;Sampson JH;Mitchell DA
尽管采取积极的常规治疗，多形性胶质母细胞瘤（GBM）仍然是致命的。免疫疗法利用免疫系统特异性攻击恶性细胞，提供了一种毒性较小的治疗选择。 GBM 中巨细胞病毒 (CMV) 抗原的表达为靶向这些病毒蛋白进行肿瘤免疫治疗提供了独特的机会。尽管多个实验室已证实恶性胶质瘤内存在 CMV，但其作为 GBM 免疫靶点的相关性尚未确定。本研究的目的是探讨 CMV pp65 RNA 转染的树突状细胞 (DC) 刺激的 T 细胞是否以抗原特异性方式靶向并消除自体 GBM 肿瘤细胞。用 CMV pp65 RNA 脉冲的自体 DC 刺激 GBM 患者的 T 细胞，并测量效应 CMV pp65 特异性 T 细胞的功能。在这项研究中，我们证明了使用从新诊断的 GBM 患者产生的 RNA 脉冲自体 DC 在体外引发 CMV pp65 特异性免疫反应的能力。重要的是，CMV pp65 特异性 T 细胞以抗原特异性方式裂解自体原代 GBM 肿瘤细胞。此外，使用总肿瘤RNA脉冲的DC在体外扩增T细胞，通过四聚体分析以及对表达CMV pp65的靶细胞的识别和杀伤进行评估，结果显示CMV pp65特异性T细胞扩增了10-20倍。这些数据共同证明，CMV 特异性 T 细胞可以有效地靶向胶质母细胞瘤肿瘤细胞进行免疫杀伤，并支持在 GBM 患者中开发 CMV 定向免疫疗法的基本原理。
Despite aggressive conventional therapy, glioblastoma multiforme (GBM) remains uniformly lethal. Immunotherapy, in which the immune system is harnessed to specifically attack malignant cells, offers a treatment option with less toxicity. The expression of cytomegalovirus (CMV) antigens in GBM presents a unique opportunity to target these viral proteins for tumor immunotherapy. Although the presence of CMV within malignant gliomas has been confirmed by several laboratories, its relevance as an immunological target in GBM has yet to be established. The objective of this study was to explore whether T cells stimulated by CMV pp65 RNA-transfected dendritic cells (DCs) target and eliminate autologous GBM tumor cells in an antigen-specific manner. T cells from patients with GBM were stimulated with autologous DCs pulsed with CMV pp65 RNA, and the function of the effector CMV pp65-specific T cells was measured. In this study, we demonstrate the ability to elicit CMV pp65-specific immune responses in vitro using RNA-pulsed autologous DCs generated from patients with newly diagnosed GBM. Importantly, CMV pp65-specific T cells lyse autologous, primary GBM tumor cells in an antigen-specific manner. Moreover, T cells expanded in vitro using DCs pulsed with total tumor RNA demonstrated a 10–20 fold expansion of CMV pp65-specific T cells as assessed by tetramer analysis and recognition and killing of CMV pp65-expressing target cells. These data collectively demonstrate that CMV-specific T cells can effectively target glioblastoma tumor cells for immunologic killing and support the rationale for the development of CMV-directed immunotherapy in patients with GBM.