响应可溶性MICA的人工嵌合受体修饰NK92细胞的抗肿瘤活性研究.pdf

目 录 摘要·····························································································1 Abstract·························································································3 前言·····························································································6 材料与方法····················································································9 结果 ··························································································21 讨论 ··························································································31 结论···························································································34 附图···························································································35 参考文献·····················································································37 综述：NKG2D/NKG2DLs在NK 细胞肿瘤免疫治疗中的研究··················42 参考文献·····················································································54 附录···························································································63 攻读学位期间发表文章情况·····························································64 致谢···························································································65 个人简历·····················································································66 新乡医学院硕士学位论文 响应可溶性MICA 的人工嵌合受体修饰NK92细胞的抗肿瘤活 性研究 摘 要 背景 免疫逃逸是癌症难以治愈最重要的特征之一。如何采取有效手段重启被肿瘤免 疫逃逸所阻断的免疫反应，调动免疫细胞对肿瘤细胞的主动杀伤，成为根治肿瘤的 关键问题。基于该理念，以嵌合抗原受体改造T/NK 细胞 （CAR-T/NK）为代表的肿 瘤免疫疗法已取得了肿瘤治疗的新突破。然而，近期发现经CAR-T 治疗的患者出现 较多预后复发案例，这与肿瘤细胞表面抗原丢失造成的免疫逃逸有关。因此，如何 应对肿瘤表面抗原丢失所产生的免疫逃逸成为肿瘤免疫疗法尤其是新一代CAR设计 亟待解决的问题。 目的 分析NKG2D 与配体复合物的蛋白质结构，设计并构建出兼具膜结合型MICA 和可溶性MICA（sMICA）靶向识别与响应能力的嵌合抗原受体，探讨该受体对sMICA 的响应能力，为增强NK92 细胞的抗肿瘤活性研究提供理论依据。 方法 以NK 细胞主要活化受体NKG2D 为CAR 的构