Immune resistance to glioma via dendritic cells

描述（由申请人提供）：我的目标是了解对胶质瘤细胞的适应性和先天免疫反应，并确定利用免疫系统抵抗儿童这些肿瘤的方法。在目前的治疗方式下，脑瘤儿童的预后仍然很差，脑瘤现在是实体瘤儿童癌症相关死亡率和发病率的主要原因。树突状细胞（dc）是一种有效的抗原呈递细胞，在启动和调节先天免疫和适应性免疫中起着重要作用。它们可以加工和呈递来自垂死肿瘤细胞的肿瘤抗原以诱导肿瘤特异性杀伤T细胞，而装载a-半乳糖神经酰胺的dc能够刺激自然杀伤T细胞（NKT）。我的假设是同时利用T细胞和NKT细胞对最佳抗神经胶质瘤免疫至关重要。这个应用程序建立在我在实验室中得到的两组发现的基础上。首先，单克隆抗体包被肿瘤细胞可以增强dc对肿瘤抗原的呈递。第二，胶质瘤患者的NKT细胞是功能性的，可以被激活介导cdld阳性胶质瘤细胞的裂解。有趣的是，cdld在肿瘤血管上也过表达，可能允许这些免疫效应物介导抗血管生成。提出的研究计划的具体目的是：1。为了表征神经胶质瘤患者的CDld限制性不变性NKT细胞反应，2)优化神经胶质瘤细胞中肿瘤抗原的递呈。寻找T细胞和NKT细胞在抗胶质瘤反应中的协同作用。本K08的教学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、研讨会和会议进行的广泛教学。提出的实验将使我获得关于胶质瘤的先天免疫和适应性免疫的新信息，如何测量它，如何优化抗原呈递，并确定我们是否可以通过同时刺激先天和适应性免疫系统来增强抗胶质瘤免疫。上述实验的结果将为开发一种新的基于免疫的诊断和治疗这些儿童的方法提供基线。结合教育计划，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.