OVERCOMING TUMOR TOLERANCE THROUGH IN VIVO GENERATED DENDRITIC CELLS

通过体内生成的树突状细胞克服肿瘤耐受性

• 批准号: 7720483
• 负责人: YAN CUI
• 金额: $ 13.8万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7720483
• 关键词: Address; Antigens; Cancer Immunology Science; Computer Retrieval of Information on Scientific Projects Database; Data; Dendritic Cells; Dose; ERBB2 gene; Funding; Gene-Modified; Genes; Grant; Hemagglutinin; Immune; Institution; Numbers; Research; Research Personnel; Resources; Role; Site; Source; System; T-Lymphocyte; Testing; Tumor Antigens; Tumor Immunity; United States National Institutes of Health; Work; anergy; cancer immunology function; cell type; concept; in vivo; innovation; novel; tumor; vector

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In this project, we are developing a new strategy to specifically target tumor antigen gene to in vivo derived DCs in great number to stimulate substantial and sustained immune activation. This concept has been tested using foreign antigens such as hemagglutinin, however testing this concept with tumor antigens in a tumor microenvironment has been difficult. Our preliminary data suggest that using specific vectors may control the amount and type of antigen being presented in vivo. Thus, our central hypothesis is that "in vivo generated, tumor antigen gene modified DCs will provide sustained stimulation and induce a strong anti-tumor immunity capable of tumor elimination". The work proposed is highly innovative and will test this hypothesis in two specific aims using a native tumor antigen HER2/neu. First, she will test the hypothesis that in vivo derived HER2/neu expressing dendritic cells can stimulate a strong immune activation to overcome tolerance, using specific vectors that allow controlled and regulated antigen expression in specific cell types. Second, with this system she will test the hypothesis that this strong activation will result in sufficient recruitment of antigen specific effector T cells to tumor sites for tumor elimination. This project not only addresses the mechanisms of tumor induced anergy, a major field of research in cancer immunology, but also explores a novel concept, i.e. the roles of antigen dose, DC activation status and persistence in vivo in overcoming tumor induced tolerance.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 在这个项目中，我们正在开发一种新策略，将肿瘤抗原基因特异性靶向体内衍生的大量树突状细胞，以刺激大量且持续的免疫激活。这个概念已经使用血凝素等外来抗原进行了测试，但是在肿瘤微环境中用肿瘤抗原测试这个概念一直很困难。我们的初步数据表明，使用特定载体可以控制体内呈递的抗原的数量和类型。因此，我们的中心假设是“体内产生的、肿瘤抗原基因修饰的DC将提供持续的刺激并诱导能够消除肿瘤的强大的抗肿瘤免疫”。所提出的工作具有高度创新性，并将使用天然肿瘤抗原 HER2/neu 在两个特定目标中测试这一假设。首先，她将测试以下假设：体内衍生的 HER2/neu 表达树突状细胞可以刺激强烈的免疫激活以克服耐受性，使用允许在特定细胞类型中控制和调节抗原表达的特定载体。其次，她将利用这个系统来测试这样的假设：这种强烈的激活将导致抗原特异性效应 T 细胞充分募集到肿瘤部位以消除肿瘤。该项目不仅解决了肿瘤诱导的无反应性这一癌症免疫学研究的主要领域的机制，而且还探索了一个新的概念，即抗原剂量、DC激活状态和体内持久性在克服肿瘤诱导的耐受性中的作用。