Immune resistance to glioma via dendritic cells

描述(申请人提供)：我的目标是了解对胶质瘤细胞的适应性和先天免疫反应，并找出利用免疫系统抵抗儿童肿瘤的方法。在目前的治疗方式下，脑瘤儿童的预后仍然很差，脑瘤现在是导致实体瘤儿童癌症相关死亡和发病率的主要原因。树突状细胞(DC)是启动和调节天然免疫和获得性免疫的重要抗原提呈细胞。它们可以处理和呈递来自死亡肿瘤细胞的肿瘤抗原，以诱导肿瘤特异性杀伤T细胞，而负载α-半乳糖神经酰胺的DC能够刺激自然杀伤T(NKT)细胞。我的假设是，同时利用T细胞和NKT细胞对于最佳的抗胶质瘤免疫至关重要。这个应用程序建立在我在实验室中的两组发现之上。首先，通过用单抗包裹肿瘤细胞，可以增强DC对肿瘤抗原的呈递。其次，胶质瘤患者的NKT细胞具有功能，并可被激活以介导CD-LD阳性胶质瘤细胞的溶解。有趣的是，CD_1d在肿瘤血管上也过度表达，潜在地允许这些免疫效应器介导抗血管生成。提出的研究计划的具体目的是：1.研究胶质瘤患者CDLD限制性不变NKT细胞应答的特征；2)优化DC提呈胶质瘤细胞的肿瘤抗原；3.寻找T细胞和NKT细胞应答在抗胶质瘤中的协同作用。这个K08的教育计划包括免疫学和临床研究方法的实验室经验，以及通过课程作业、研讨会和会议进行广泛的教学。拟议的实验将使我获得关于胶质瘤的先天免疫和获得性免疫的新信息，如何测量它，如何优化抗原提呈，并确定我们是否可以通过同时刺激先天免疫系统和获得性免疫系统来增强抗胶质瘤免疫。上述实验结果将为开发一种新的基于免疫的儿童诊断和治疗方法提供基线。加上教育计划，我最终应该能够在这个令人兴奋的领域领导一个独立的实验室。

DESCRIPTION (provided by applicant): My goal is to understand the adaptive and innate immune responses to glioma cells, and to identify ways to harness the immune system to resist these tumors in children. The prognosis for children with brain tumors remains poor with current modalities of treatment and brain tumors are now the leading cause of cancer related mortality and morbidity in children with solid tumors. Dendritic cells (DCs) are potent antigen presenting cells central to initiating and regulating both innate and adaptive immunity. They can process and present tumor antigens from dying tumor cells to elicit tumor specific killer T cells and DCs loaded with a-Galactosylceramide are able to stimulate Natural killer T (NKT) cells. My hypothesis is that harnessing both T and NKT cells is critical to optimal anti-glioma immunity. This application builds on two sets of findings that I have made in the lab. First that presentation of tumor antigens by the DCs can be enhanced by coating of the tumor cells with monoclonal antibodies. Second, that the NKT cells in glioma patients are functional and can be activated to mediate lysis of CD ld positive g lioma cells. Interestingly, CD ld is also overexpressed on tumor vessels, potentially allowing for these immune effectors to mediate anti-angiogenesis. The specific aims of the proposed research plan are 1. To characterize the CDld restricted invariant NKT cell response in patients with glioma, 2) optimize presentation of tumor antigens from glioma cells by DCs and 3. To look for cooperation between T and NKT cell response in resisting glioma. The educational plan of this K08 includes laboratory experience in immunological and clinical research methods along with extensive didactic teaching through coursework, seminars and conferences. The proposed experiments will allow me to gain new information on innate and adaptive immunity to glioma, how to measure it, how to optimize antigen presentation, and to determine whether we can enhance anti-glioma immunity by simultaneous stimulation of the innate and adaptive immune system. The results of the above experiments will provide the baseline for the development of a novel immune based approaches for diagnosis and treatment in these children. Together with the educational plan, I should ultimately be able to lead an independent laboratory in this exciting field.