Transgene-enforced co-stimulation of CD4+ T cells leads to enhanced and sustained anti-tumor effector functioning
Transgene-enforced co-stimulation of CD4+ T cells leads to enhanced and sustained anti-tumor effector functioning
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DOI：
10.1080/14653240701656079
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发表时间：
2007-01-01
期刊：
影响因子：
4.5
通讯作者：
Jensen, M. C.
中科院分区：
文献类型：
--
作者：
Chang, L.;Chang, W. C.;Jensen, M. C.
背景共刺激在CD 4（+）T细胞通过专职APC活化中的作用已被充分确立，而当CD 4 + T细胞直接与肿瘤细胞相互作用时，共刺激所起的作用知之甚少。IL-13 R α 2-特异性IL-13-zetakine结果与单独的CD 3 zeta介导的活化相比，表达IL 13-CD 28 - 41 BB zeta CAR的CD 4（+）效应T细胞表现出增强/持续的MAPK和AKT活性，上调Th 1细胞因子的产生，并增强对肿瘤靶点的细胞溶解效力。此外，在用肿瘤递归刺激后，IL-13-CD 28 - 41 BB zeta（+）细胞保留/再循环其裂解功能，而IL-13 C（+）CD 4（+）细胞变得无反应性/耗尽。这些体外观察结果与免疫缺陷小鼠中建立的原位CNS神经胶质瘤异种移植物的体内控制增强相关，所述免疫缺陷小鼠由表达共刺激CAR.DiscussionTogether的过继转移的体外扩增的CD 4（+）T细胞介导，这些研究证明了将共刺激与CD 3 zeta信号传导事件整合以充分激活CD 4（+）抗肿瘤效应细胞以在肿瘤微环境中持续发挥功能的重要性。
Background Thc role of co-stimulation in CD4(+) T cell activation by professional APC is well established, while less is known of the role co-stimulation plays when CD4+ T cells interact directly with tumor cells.MethodsThrough generic engineering of human CD4(+) T cells We tested the hypothesis that integration of co-stimulatory signaling domains within a tumor-targeting chimeric Ag receptor (CAR), the IL-13R alpha 2-specific IL-13-zetakine (IL13 zeta), would enhance CD4(+) T cell mediated responses against tumors that fail to express ligands for co-stimulatory receptors.ResultsCompared with CD3 zeta-mediated activation alone, CD4(+) effector T cells expressing the IL13-CD28-41BB zeta CAR exhibited augmented/ sustained MAPK and AKT activity, up-regulated Th1 cytokine production, and enhanced cytolytic potency against tumor targets. Moreover, upon recursive stimulation with tumor the IL13-CD28- 41BB zeta(+) cells retained/recycled their lytic function, whereas IL-13C(+) CD4(+) cells became anergic/exhausted. These in vitro observations correlated with enhanced in vivo control of established orthotopic CNS gliomia xenografts in immunodeficient mice mediated by adoptively transferred ex vivo-expanded CD4(+) T cells expressing the co-stimulatory CAR.DiscussionTogether these studies demonstrate the importance of integrating co-stimulation with CD3 zeta signaling events to activate fully CD4(+) antitumor effector cells for sustained function in the tumor microenvironment.