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

描述（由申请人提供）：我们研究的广泛，长期目标是：i)开发和优化基于树突状细胞的免疫治疗脑肿瘤的方法；ii)更好地理解以树突状细胞为基础的靶向中枢神经系统（CMS）肿瘤的策略所产生的免疫反应机制。为此，我们提出了三个具体目标，旨在了解临床前动物模型和临床患者样本中对CMS肿瘤根除至关重要的抗肿瘤免疫机制。神经胶质瘤的免疫治疗传统上落后于其他周围肿瘤，其中明确的CTL靶点是已知的。在我们最近的临床前研究中，我们已经表明人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在胶质瘤和黑色素瘤中的共同表达源于它们共同的神经外胚层起源。我们的发现很重要，因为它确定了胶质瘤上的一组内源性肿瘤相关抗原（TAA），这些抗原具有很好的细胞毒性T淋巴细胞（CTL）表位。利用我们的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研究，不仅测试靶向MAA对CMS肿瘤的治疗价值，而且提供了一个模型来测试对位于中枢神经系统的内源性MAA产生抗肿瘤免疫的基本免疫需求。我们的中心假设是中枢神经胶质瘤表达MAA，可以通过免疫疗法靶向，增强T细胞和DC的激活和运输。因此，这是一个机械和转化项目，与我们上述长期目标和促进公众健康的使命直接相关。

DESCRIPTION (provided by applicant): 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.