NK细胞肿瘤免疫增敏化合物筛选及机制研究

	NK细胞肿瘤免疫增敏化合物筛选及机制研究; Study on active molecules that promote susceptibility of cancer cells to NK cell mediated cytolysis
	朱怡颖
导师	周宏宇
摘要	Natural killer （NK）cells are important lymphocytes that can defend body and regulate immune system. The activating receptor NKG2D （natural killer group 2, member D） of natural killer （NK） cells promotes tumor immune surveillance by targeting ligands specifically induced on tumor cells, and playing a crucial role in the prevention and treatment of tumors. Immune-edited tumors can evade NK cell-mediated killing via down-regulation of NKG2D ligands on their surface. Consequently, increasing expression of NKG2D ligands on tumor cells and thus promoting the killing activity of NK cells could enhance anti-tumor immunity effectively. The research work of this paper includes two parts: In the first part, based on the detection of the expression of NKG2D ligands on the surface of tumor cells, we screened 54 compounds in the natural product library. It was found that compounds 1 and 2 initially showed certain activities and could upregulate the protein expression level of MICA/B on the surface of colorectal cancer HCT-116 cells, and further research on the mechanism of action is still in progress. In the second part, we investigated the mechanisms for Ciclopirox Olamine （CPX） up-regulating the expression of NKG2D ligands on leukemia. CPX is a small molecular compound first found in laboratory that can significantly enhance the tumor immune activity of NK cells. First of all, we confirmed that CPX could upregulate the expression of NKG2D ligands and sensitize its recognition and lysis by NK cells. Molecular regulatory mechanism studies have shown that CPX upregulates the expression of NKG2D ligand by two different means. On the one hand, CPX inhibits the shedding of major histocompatibility complexs class Ⅰ molecules （MHC-Ⅰ） related protein B （MICB） by inhibiting the activity of matrix metalloproteinase 9 （MMP9）. On the other hand, CPX promotes the generation of reactive oxygen species （ROS） and enhances the mRNA expression level of each ligand of NKG2D. This regulation is in line with the phosphorylation level of protein kinase B （AKT）. Overall, this study focused on the screening and mechanism of NK cell immunosensitization active molecules, and found two active molecules that can promote the expression of NKG2D ligands. The mechanism of the active compound CPX was clarified, which laid an important foundation for its in-depth research and development as an immunomodulator.
	2021-05
文献类型	学位论文
条目标识符	http://ir.kib.ac.cn/handle/151853/74496
专题	昆明植物所硕博研究生毕业学位论文
推荐引用方式 GB/T 7714	朱怡颖. NK细胞肿瘤免疫增敏化合物筛选及机制研究, Study on active molecules that promote susceptibility of cancer cells to NK cell mediated cytolysis[D],2021.

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