溶瘤NDV经NKp46调控NK细胞膜型因子受体表达促其抗肝癌机制研究

溶瘤病毒治疗已成为肿瘤治疗重要的辅助手段，研究表明溶瘤病毒家族的新城疫病毒（NDV）抗瘤作用不但与其直接溶瘤有关，也与NDV激活免疫有关，且近年病毒活化NK细胞抗肿瘤研究越来越受重视。此前我们证实：在增强NK细胞抗小鼠实验肝癌中，NDV存在HN-NKp46直接活化途径，然而此途径是否为NDV调控γ干扰素受体在内的膜型受体的活化机制，并不十分清楚。基于前期研究，我们提出假说：NDV经NKp46调控NK细胞膜型因子受体表达促其抗小鼠实验肝癌作用。为此，本项目拟以“直接活化途径”为切入点，进行如下探讨：1.NKp46在NK细胞介导的NDV抗肿瘤免疫中的作用；2.NKp46途径调控的膜型因子受体及其在NDV抗肿瘤免疫中的作用；3.NKp46调控细胞因子受体的信号通路事件。项目的完成将有助于我们对NDV抗瘤的免疫活化机制认识，也为基于“NDV/NDV-HN-NK细胞”肿瘤生物治疗提供新的理论基础。

The oncolytic virus possesses antitumor activity and is relatively safe for the host, promising an ideal candidate for tumor biotherapy. The antitumor mechanisms of oncolytic Newcastle disease virus (NDV) include apoptosis and autophagy in tumor cells and its ability to stimulate immunoreactive cells. In recent years, more and more attention about oncolytic virus has been paid to the ability to stimulate natural killer (NK) cells for tumoricidal activity. We previously showed that exposure of NK cells to NDV resulted in enhanced tumoricidial activity of mouse experimental liver cancer which was mediated by upregulated expression of the TRAIL gene, via NKp46 pathway. Cytokine receptor genes upregulation via NKp46 pathway are yet to be identified. Based on previous research work, we hypothesized that NDV upregulates expression of cytokine receptor genes in murine NK cells via NKp46 pathway contributing to the antitumor effect. So we will use molecular biology and other techniques to perform the following work: ①The study on antitumor effect of NDV via NKp46-dependent pathway is investigated.②The upregulation of cytokine receptor genes and its antitumor effect for mouse experimental liver cancer are investigated based on NKp46-dependent manner in NDV-stimulated NK cells. ③The signal events involved are investigated. This project will highlight the immunostimulatory capabilities of NDV upon oncolytic activity and innate immune response mediated by NK cells. Our results will provide insights into tumor immunotherapy based on NDV-NK or NDV-HN-NK stimulation.