Engineered drug resistant γδ T cells kill glioblastoma cell lines during a chemotherapy challenge: a strategy for combining chemo- and immunotherapy.
Engineered drug resistant γδ T cells kill glioblastoma cell lines during a chemotherapy challenge: a strategy for combining chemo- and immunotherapy.
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DOI：
10.1371/journal.pone.0051805
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Spencer HT
中科院分区：
文献类型：
--
作者：
Lamb LS Jr;Bowersock J;Dasgupta A;Gillespie GY;Su Y;Johnson A;Spencer HT
经典的免疫治疗方法在某些恶性肿瘤中显示出希望，但在应用于高级别脑肿瘤如多形性胶质母细胞瘤（GBM）时通常令人失望。我们最近发现，离体扩增/活化的γδ T细胞识别恶性胶质瘤上表达的NKG 2D配体，并且对胶质瘤细胞系和原代GBM外植体具有细胞毒性。此外，当给予具有颅内人神经胶质瘤异种移植物的免疫缺陷小鼠时，γδ T细胞延长存活期并减缓肿瘤进展。我们现在发现，替莫唑胺（TMZ），一种用于治疗GBM的主要化疗药物，增加了TMZ耐药胶质瘤细胞上应激相关NKG 2D配体的表达，可能使其易受γδ T细胞识别和裂解的影响。然而，TMZ对γδ T细胞也具有高毒性，为了克服这种细胞毒性效应，使用编码来自O（6）-甲基鸟嘌呤甲基转移酶（MGMT）cDNA的DNA修复酶O（6）-烷基鸟嘌呤DNA烷基转移酶（AGT）的慢病毒载体对γδ T细胞进行遗传修饰，其赋予对TMZ的抗性。γδ T细胞的遗传修饰不改变其表型或其对GBM靶细胞的细胞毒性。重要的是，在TMZ存在下，基因修饰的γδ T细胞对两种TMZ抗性GBM细胞系U373 TMZ-R和SNB-19 TMZ-R细胞显示出比未修饰的细胞更大的细胞毒性，表明TMZ暴露了更多的γδ T细胞靶向裂解的受体。因此，在高浓度TMZ存在下，可以产生TMZ抗性γδ T细胞而不损害其抗肿瘤功能。这些结果为联合化疗和基于γδ T细胞的耐药细胞免疫治疗GBM提供了机制基础。
Classical approaches to immunotherapy that show promise in some malignancies have generally been disappointing when applied to high-grade brain tumors such as glioblastoma multiforme (GBM). We recently showed that ex vivo expanded/activated γδ T cells recognize NKG2D ligands expressed on malignant glioma and are cytotoxic to glioma cell lines and primary GBM explants. In addition, γδ T cells extend survival and slow tumor progression when administered to immunodeficient mice with intracranial human glioma xenografts. We now show that temozolomide (TMZ), a principal chemotherapeutic agent used to treat GBM, increases the expression of stress-associated NKG2D ligands on TMZ-resistant glioma cells, potentially rendering them vulnerable to γδ T cell recognition and lysis. TMZ is also highly toxic to γδ T cells, however, and to overcome this cytotoxic effect γδ T cells were genetically modified using a lentiviral vector encoding the DNA repair enzyme O(6)-alkylguanine DNA alkyltransferase (AGT) from the O(6)-methylguanine methyltransferase (MGMT) cDNA, which confers resistance to TMZ. Genetic modification of γδ T cells did not alter their phenotype or their cytotoxicity against GBM target cells. Importantly, gene modified γδ T cells showed greater cytotoxicity to two TMZ resistant GBM cell lines, U373TMZ-R and SNB-19TMZ-R cells, in the presence of TMZ than unmodified cells, suggesting that TMZ exposed more receptors for γδ T cell-targeted lysis. Therefore, TMZ resistant γδ T cells can be generated without impairing their anti-tumor functions in the presence of high concentrations of TMZ. These results provide a mechanistic basis for combining chemotherapy and γδ T cell-based drug resistant cellular immunotherapy to treat GBM.
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影响因子：
11.5
作者：
Arlen, PM;Gulley, JL;Dahut, W
通讯作者：
Dahut, W
影响因子：
15.9
作者：
Bryant, Nichole L.;Suarez-Cuervo, Catalina;Lamb, Lawrence S., Jr.
通讯作者：
Lamb, Lawrence S., Jr.
影响因子：
56.9
作者：
Bauer, S;Groh, V;Spies, T
通讯作者：
Spies, T
影响因子：
12.4
作者：
Doering, Christopher B.;Denning, Gabriela;Spencer, H. Trent
通讯作者：
Spencer, H. Trent
影响因子：
8.8
作者：
Farkkila, M;Jaaskelainen, J;Kallio, M;Blomstedt, G;Raininko, R;Virkkunen, P;Paetau, A;Sarelin, H;Mantyla, M
通讯作者：
Mantyla, M