Genome Instability Induced Anti-Tumor Immune Responses

摘要 本计划项目拨款的首要目标是了解基本知识 癌细胞基因组不稳定性与免疫之间的联系机制 系统。研究人员在P01上所做的基础工作展示了在 哪种基因组损伤被模式识别受体异常地检测为“外来” 通常用于检测病毒核酸。来自我们小组的集体工作 确定DNA损伤、组织结构改变、有丝分裂错误和核膜 脆弱性打破了细胞固有的屏障，阻止内源性DNA和RNA 通过先天免疫模式识别传感器进行检测。这些事件严重影响了肿瘤。 促进或抑制肿瘤生长的微环境。为了实现我们的目标，我们有 组装了三个项目，将与三个核心密切合作，以解决以下关键问题 通过免疫反应检测肿瘤基因组的不稳定性。项目1调查 DNA损伤反应与内源DNA和DNA模式识别的关系 细胞质中的核糖核酸。项目2测试了关于组织结构和组织结构的破坏如何 机械力会导致染色体的错误分离和不稳定。它描述了一种方法 以了解先天免疫系统对这种不稳定性的识别。项目3在体内进行研究 对肿瘤内DNA损伤的反应，同时设计合理的方法来增强抗 肿瘤免疫激活。将这些多学科项目与哺乳动物人工制品相结合 染色体和化学生物学核心将推进我们定义分子的主要目标 为免疫检测癌症基因组不稳定性奠定了基础。

Summary The overarching objective of this Program Project Grant is to understand fundamental mechanisms underlying communication between cancer cell genomic instability and the immune system. Foundational work from the investigators on this P01 demonstrates multivariate ways in which genomic damage is aberrantly detected as “foreign” by pattern recognition receptors that are typically used to sense viral nucleic acids. The collective body of work from our groups establish that DNA damage, changes in tissue architecture, mitotic errors, and nuclear envelope fragility serve to breach cell intrinsic barriers that prevent endogenous DNA and RNA from detection by innate immune pattern recognition sensors. These events critically affect the tumor microenvironment to either promote or suppress tumor growth. To achieve our goals, we have assembled three Projects that will work closely with three Cores to address critical questions on detection of genome instability in tumors by the immune response. Project 1 investigates the relationship between DNA damage responses and pattern recognition of endogenous DNA and RNA in the cytoplasm. Project 2 tests hypotheses on how disruption in tissue architecture and mechanical forces result in chromosome missegregation and instability. It describes an approach to understand innate immune system recognition of this instability. Project 3 investigates in vivo responses to DNA damage within tumors, while designing rational approaches to enhance anti- tumor immune activation. Integration of these multidisciplinary projects with Mammalian Artificial Chromosome and Chemical Biology Cores will advance our primary goal of defining the molecular basis for immune detection of genome instability in cancer.