LSUHSC COBRE:PROJ 2: OVERCOMING TUMOR TOLER THROUGH IN VIVO GEN* DENDRITIC CELLS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。通过体内产生的树突状细胞克服肿瘤耐受性：有效免疫治疗的主要障碍之一是现有的T细胞对肿瘤抗原的耐受性或无反应性。最近，巨大的努力已经集中在树突状细胞（DC）为基础的疫苗使用离体操作的DC。虽然这些常规DC疫苗方法在增强抗原呈递和T细胞活化方面显示出有希望的结果，但它们未能提供足够和持续的免疫活化以克服肿瘤耐受性，部分原因是有限数量的离体操纵的抗原呈递DC到达适当的淋巴区室。本研究开发了一种新的策略，将肿瘤抗原基因特异性靶向于体内大量来源的DC，以刺激大量和持续的免疫激活。已经使用外源抗原如血凝素测试了这个概念，然而在肿瘤微环境中用肿瘤抗原测试这个概念是困难的。我们的初步数据表明，使用特定的载体可以控制在体内呈递的抗原的量和类型。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抗肿瘤免疫”。提出的工作是高度创新的，并将使用天然肿瘤抗原HER 2/neu在两个特定目标中测试这一假设。首先，她将测试体内衍生的HER 2/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的假设，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。第二，利用该系统，她将检验这样的假设，即这种强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的机制，这是癌症免疫学的主要研究领域，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. Overcoming Tumor Tolerance through in vivo generated dendritic cells: One of the major hurdles for effective immunotherapy treatment is the existing T cell tolerance or anergy to tumor antigens. Recently, tremendous efforts have been focused on dendritic cells (DC) based vaccine using ex vivo manipulated DCs. While these conventional DC vaccine approaches showed promising outcomes in enhancing antigen presentation and T cell activation, they failed to provide sufficient and sustained immune activation to overcome tumor tolerance, in part due to the limited number of ex vivo manipulated antigen presenting DCs reaching appropriate lymphoid compartment. Here we developed 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.