CUTTING EDGE LINEAGE TRACKING OF TUMOR-EDUCATED IMMUNE CELLS

 描述(由申请人提供)：可悲的是，我们不知道哪些宿主细胞在肿瘤中受到教育，并对远端部位有贡献。此外，尽管特定的免疫细胞(如髓系细胞)很可能进入远端淋巴结，但这类细胞的关键特征(其身份寿命、自我更新、特定功能)仍未得到解决。值得注意的是，我们目前还不能知道转移部位的哪些宿主细胞在原发肿瘤中滞留后最先到达。在这项应用中，我们将开发新技术，在细胞及其后代的整个生命周期内，追踪细胞从一个器官到所有其他器官的世系。我们将利用这一点来测试免疫细胞，特别是那些髓系细胞，在 肿瘤微环境和远处部位的组成，如淋巴结、脾和可能的转移部位；此外，我们将确定这种贡献的功能后果。值得注意的是，这将是第一次直接和明确地展示哪些细胞运输到引流淋巴结并在引流淋巴结中呈递抗原，整个血统的点对点图谱，发现从哪些细胞运输出来的新血统。 肿瘤和转移部位是否含有曾经位于另一个病变内的免疫细胞的测试。这项技术解决了现有可光切换方法的主要缺陷，并将尖端的实时成像方法广泛扩展到血统追踪。

 DESCRIPTION (provided by applicant): We are woefully ignorant of which host cells are educated in the tumor and contribute to distal sites. Further, although it is very likely that specific immune cells (e.g. myeloid) travel to the distal lymph nodes, key features (their identity lifespan, self-renewal, specific functions) of such cells remains unaddressed. Remarkably, we cannot currently know which host cells in a metastatic site first arrived following residence in a primary tumor. In this application we will develop new technologies to lineage-track cells from one organ to all others, over the entire lifespan of the cell and its progeny. We will use this to test the hypothesis that immune cells, particularly those of the myeloid lineage, are 'educated' in the tumor microenvironment and contribute to the composition of distant sites such as lymph node, spleen and possibly metastatic sites; furthermore we will determine the functional consequences of such a contribution. Notably, this will represent the first direct and unambigious demonstration of which cells traffic to and present antigens in draining lymph nodes, a site-to-site mapping of entire lineages, a discovery of novel lineages that traffic out of tumors and a test that metastatic sites contain immune cells that were once within another lesion. This technology solves a major deficit with existing photoswitchable approaches and broadly extends cutting edge live-imaging approaches towards lineage tracing.