CNS Anti-tumor immunity induced by dendritic cell vaccination and TLR agonists

我们研究的长期目标是：i)开发和优化树突状细胞为基础的 治疗脑肿瘤的免疫治疗方法；以及ii)更好地了解 以树突状细胞为基础的中枢神经靶向免疫应答机制 系统(CMS)肿瘤。为了做到这一点，我们提出了三个旨在理解的具体目标，这两个目标都在 临床前动物模型以及临床患者样本中抗肿瘤免疫的机制 对于CMS肿瘤的根除至关重要。胶质瘤的免疫治疗传统上落后于其他 已知CTL靶点的周围性肿瘤。在我们最近的临床前研究中，我们已经表明 人类和小鼠胶质瘤都表达黑色素瘤相关抗原(MAA)，可以 被细胞免疫系统识别。我们认为MAA在胶质瘤中的共同表达 而黑色素瘤源于它们共同的神经外胚层起源。我们的发现很重要 因为它在胶质瘤上发现了一组内源性肿瘤相关抗原(TAA)，这些肿瘤细胞 表征细胞毒性T淋巴细胞(CTL)表位。使用我们的T细胞受体转基因小鼠模型， 体内成像方法和Toll样受体(TLR)激动剂，我们设计了一套系统的 不仅测试靶向MAA对CMS肿瘤的治疗价值，而且提供了一种模型 测试产生抗肿瘤免疫的基本免疫学要求，以确定内源性 MAA位于中枢神经系统。我们的中心假设是中枢神经系统胶质瘤表达MAA，这可能是 以免疫疗法为靶点，增强T细胞和DC的激活和运输。因此，这是一个 与上述长期目标直接相关的机械化和翻译项目，以及 致力于促进公众健康的使命。

The broad, long-term objectives of our research are: i) to develop and optimize dendritic cell-based immunotherapy approaches for the treatment of brain tumors; and ii) to gain a better understanding of the mechanisms of immune responses generated by dendritic cell-based strategies targeting central nervous system (CMS) neoplasms. To do this, we propose three specific aims designed to understand, both in pre-clinical animal models as well as in clinical patient samples, the mechanisms of anti-tumor immunity critical for CMS tumor eradication. Immunotherapy for glioma has traditionally lagged behind other peripheral tumors where defined CTL targets are known. In our recent pre-clinical studies we have shown that both human and murine gliomas express melanoma-associated antigens (MAA)that can be recognized by the cellular immune system. We believe that the shared expression of MAA on gliomas and melanomas stems from their common neuroectodermal origin. Our discovery was important because it identified a set of endogenous tumor-associated antigens (TAA) on gliomas that have well characterized cytotoxic T lymphocyte (CTL) epitopes. Using our T cell receptor transgenic mouse model, in vivo imaging methodologies, and Toll-like receptor (TLR) agonists, we have designed a systematic set of studies to not only test the therapeutic value of targeting MAA on CMS tumors, but provide a model to test the basic immunological requirements for generating anti-tumor immunity to defined, endogenous MAA located in the CNS. Our central hypothesis is that CNS gliomas express MAA, which can be targeted by immunotherapies that enhance T cell and DC activation and trafficking. Thus, this is a mechanistic and translational project that is directly related to our long-term objectives stated above and to the mission of promoting public health.