Non-invasive imaging of tumor-reactive T cell subsets in vivo

描述(由申请人提供)：尽管对导致抗肿瘤免疫反应的细胞和分子相互作用有详细的了解，过继免疫治疗方法只在少数特定肿瘤类型的病例中成功。目前用于检测细胞抗肿瘤免疫反应的方法虽然有价值，但在时间和空间上都是快照，不能充分反映免疫反应的动态和多焦点性质。全身非侵入性成像模式的发展使该领域受益匪浅，这种成像模式可用于确定感兴趣细胞在动物或人类患者体内的多个位置和不同时间点的位置。我们的假设是，使用非侵入性分子成像技术来研究T细胞的运动和功能将提供使用常规方法无法获得的关于细胞抗肿瘤反应的信息，从而允许更全面地分析实现成功的抗肿瘤治疗所需的修饰。这项建议的目标是开发和验证成像工具，这些工具可以使用放射性同位素和生物发光光学成像技术在体内跟踪谱系特异性和激活依赖的抗肿瘤T细胞反应。我们将开发慢病毒载体，其中CD8+和CD4+T细胞将被选择性地标记成像报告基因。我们还将开发报告基因只有在特定亚群中的T细胞激活后才表达的结构。因此，我们将能够可视化T细胞在肿瘤部位和淋巴器官中的定位和激活。该系统将使用两个研究得很好的肿瘤模型进行验证。我们预计，该系统还可以用于研究自身免疫以及对病毒和其他病原体的反应。最后，这里建立的方法学有可能被转化到临床，用于人类患者，以评估细胞过继免疫疗法治疗癌症的疗效。对公众健康：我们开发的分子“灯塔”将允许我们看到T细胞在对肿瘤做出反应时的位置和功能。在动物模型中，我们将能够更好地了解癌症有效治疗存在的障碍。该系统有可能被转化为用于人类患者的临床，并将为医生提供一种高度敏感的测试，可用于跟踪抗癌免疫反应随时间的进展。

DESCRIPTION (provided by applicant): Despite detailed knowledge on the cellular and molecular interactions that result in an anti-tumor immune response, adoptive immunotherapy approaches are only successful in a small number of cases for certain tumor types. Current assays used to detect cellular anti-tumor immune responses while valuable, are snapshots in time and space and do not adequately reflect the dynamic and multifocal nature of the immune response. The field has benefited greatly by the development of whole-body non-invasive imaging modalities that can be used to determine the locations of cells of interest at multiple sites and at different time points within the animal or human patient. Our hypothesis is that the use of non-invasive molecular imaging techniques to study T cell movement and function will provide information regarding cellular anti- tumor responses that cannot be obtained using conventional methods, thus allowing a more comprehensive analysis of the modifications necessary to achieve successful anti-tumor therapy. The goal of this proposal is to develop and validate imaging tools that can be used to follow lineage-specific and activation dependent anti-tumor T cell responses in vivo, using radioisotopic and bioluminescent optical imaging techniques. We will develop lentiviral vectors where CD8+ and CD4+ T cells will be selectively tagged with imaging reporter genes. We will also develop constructs where the reporter genes are expressed only after T cell activation in the specific subset. Consequently, we will be able to visualize the localization and activation of T cells at the tumor site, and in lymphoid organs. The system will be validated using two well- studied tumor models. We anticipate that this system can also be used for studies of autoimmunity as well as responses against viruses and other pathogens. Finally the methodologies established here have the potential to be translated to the clinic for use in human patients to assess the efficacy of cellular adoptive immunotherapy for the treatment of cancer. TO PUBLIC HEALTH: The molecular "beacons" we develop will allow us to see the location and function of T cells as they respond to tumors. In animal models, we will be able to better understand the roadblocks that exist to effective treatment for cancer. This system can potentially be translated to use in clinics for human patients, and will provide the physician with a highly sensitive test that can be used to follow the progress of an anti- cancer immune response over time.