Immune resistance to glioma via dendritic cells

描述（由申请人提供）：我的目标是了解神经胶质瘤细胞的适应性和先天性免疫反应，并确定利用免疫系统抵抗儿童肿瘤的方法。目前的治疗方式对脑肿瘤儿童的预后仍然很差，脑肿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（Dendritic cells，DC）是一种有效的抗原提呈细胞，在启动和调节先天性免疫和适应性免疫中起着重要作用。它们可以处理和呈递来自垂死肿瘤细胞的肿瘤抗原以引发肿瘤特异性杀伤T细胞，并且负载有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，利用T和NKT细胞对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，DC对肿瘤抗原的呈递可以通过用单克隆抗体包被肿瘤细胞来增强。第二，神经胶质瘤患者中的NKT细胞是功能性的，并且可以被激活以介导CD ld阳性神经胶质瘤细胞的溶解。有趣的是，CDld也在肿瘤血管上过表达，潜在地允许这些免疫效应物介导抗血管生成。研究计划的具体目标是1。为了表征神经胶质瘤患者中CDld限制性不变NKT细胞应答，2）优化DC对来自神经胶质瘤细胞的肿瘤抗原的呈递，以及3）优化来自神经胶质瘤细胞的肿瘤抗原的呈递。探讨T细胞和NKT细胞在抗胶质瘤中的协同作用。该K 08的教育计划包括免疫学和临床研究方法的实验室经验，沿着通过课程，研讨会和会议进行广泛的教学。拟议的实验将使我获得新的信息先天和适应性免疫胶质瘤，如何测量它，如何优化抗原呈递，并确定我们是否可以提高抗胶质瘤免疫的先天和适应性免疫系统的同时刺激。上述实验的结果将为开发用于这些儿童的诊断和治疗的新的基于免疫的方法提供基线。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.