项目名称： IL-33活化的树突状细胞（DCs）诱导Th9细胞抗肿瘤效应和机制

项目编号： No.81502452

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 初晓

作者单位： 吉林大学

项目金额： 18万元

中文摘要： 以树突状细胞（DC）为基础的免疫疗法是一类非常重要的主动性抗肿瘤免疫治疗方法。遗憾的是，多年来除了sipuleucel-T外，其它DC疫苗临床疗效偏低，这成为制约抗肿瘤疫苗发展的瓶颈。因而，如何编辑DC使其诱导更高的抗肿瘤免疫反应成为亟待解决的问题。本研究发现，即使在没有外源极化因子的条件下，IL-33活化的DCs（IL33DCs）体外也显著诱导一类新发现的、具有较强抗肿瘤免疫效应的辅助性T细胞（Th9）的生成。同时，DC表面的OX40L在加入IL-33后表达显著升高，这为IL33DCs疫苗体内抗肿瘤效应的机制研究带来启示。此外，基于gene array结果，我们将通过基因敲除鼠和特异性信号分子抑制剂的联合应用，阐明IL33DCs诱导Th9极化和抗肿瘤免疫的机制。本课题将为IL-33在抗肿瘤免疫中的应用提供理论依据，同时为靶向IL-33受体信号研制新型DCs疫苗治疗肿瘤奠定基础。

中文关键词： 白细胞介素33；辅助性T细胞；树突状细胞；抗肿瘤免疫治疗；肿瘤

英文摘要： Dendritic cells (DC) based vaccine is a new method of anti-tumor immunotherapy. However, except for sipuleucel-T, the low clinical efficacy of other DC vaccine, which restricted the development of anti-cancer vaccine. T helper 9 (Th9) cells induce better antitumor efficacies than other Th cells in a murine melanoma model, indicating the importance of further investigations of strategies to induce and expand Th9 cells for tumor therapy. Dendritic cells (DCs) are the professional antigen presenting cells (APCs) and play a critical role in Th-cell induction. Our preliminary data showed that IL-33 promoted DCs to induce Th9-cell differentiation. Further investigation showed that IL-33-conditioned DCs (IL33DCs) promoted Th9 development even at the condition of no addition of Th9 polarizing cytokines in the cultures. These results indicate that IL-33 promoteTh9 cell differentiation through IL33DCs. We found that IL33DCs have increased expression of OX40L compared to regular DCs (BMDCs). Previous investigations showed that OX40L/OX40 signaling enhances Th9 cell development. Based on these observations, we hypothesize that IL33DCs promote Th9 development and antitumor immunity through upregulation of OX40L expression. We will determine the role of IL33DCs in Th9 cell development and clarify the mechanisms of IL33DC-mediated Th9 differentiation; we will also examine the efficacy of IL33DC-based vaccines in the tumor immunotherapy and clarify the mechanisms of IL33DC-induced antitumor activities. Successful completion of these studies will help us better understand the mechanisms of IL33DCs in priming Th9 cells and antitumor immunity, providing important preclinical data for the clinical use of IL33DC-based vaccines in tumor therapy.

英文关键词： Interleukin-33;T helper cells;Dendritic cells;Anti-tumor immunotherapy;Tumor