OVERCOMING TUMOR TOLERANCE THROUGH IN VIVO GENERATED DENDRITIC CELLS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 在这个项目中，我们正在开发一种新的策略，将肿瘤抗原基因特异性地靶向大量体内来源的树突状细胞，以刺激大量和持续的免疫激活。这一概念已经用血凝素等外来抗原进行了测试，但在肿瘤微环境中用肿瘤抗原测试这一概念一直很困难。我们的初步数据表明，使用特定的载体可以控制体内呈现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，并诱导强大的抗肿瘤免疫能力，能够消除肿瘤”。提出的这项工作具有很高的创新性，将使用天然肿瘤抗原HER2/neu在两个特定目标上测试这一假说。首先，她将使用允许特定细胞类型中受控和调节抗原表达的特定载体，测试体内来源的表达HER2/neu的树突状细胞可以刺激强大的免疫激活来克服耐受性的假设。其次，利用这个系统，她将检验这样一种假设，即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。该项目不仅探讨了肿瘤诱导无能的机制，这是肿瘤免疫学的一个主要研究领域，而且探索了一个新的概念，即抗原剂量、DC激活状态和体内持续时间在克服肿瘤诱导耐受中的作用。

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.