IL-33活化的树突状细胞（DCs）诱导Th9细胞抗肿瘤效应和机制

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.

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。

前期研究发现，Dectin1 信号活化的 DCs（CurDC）在小鼠体内外都发挥强有力的抗肿瘤作用。IL-33 在 Dectin1 信号活化的 DCs 中表达显著增加。由于.IL33DC 的体内抗肿瘤结果与预期并不一致，因而我们对本课题的研究内容做了一些调整。本研究结果表明，IL-33 活化的 DCs 具有潜在的抗肿瘤作用，而其相关机制可.能与促进抗肿瘤相关 Tc 细胞的分化以及具有细胞毒作用的效应分子的表达有关。众所周知，在恶性肿瘤发生过程中常会伴发有溶骨性骨病的发生，如黑色素瘤。溶骨性骨病中的骨破坏、病理性骨折和高钙血症对病人的存活率和生活质量影响较大。IL33 可以显著促进破骨细胞的分化，这将为骨髓瘤引起的骨病有一定的抑制作用。我们将在以后的实验中进一步的验证。