Genome Instability Induced Anti-Tumor Immune Responses

基因组不稳定性诱导的抗肿瘤免疫反应

基本信息

批准号：
10626281
负责人：
Roger A Greenberg
金额：
$ 170.39万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-08 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10626281
关键词：
3-Dimensional Acute Address Affect Agreement Aneuploidy Architecture Artificial Mammalian Chromosomes BRCA2 gene Basic Science Biology Cancer Control Cells Chemicals Chromosomal Instability Chromosome Segregation Collaborations Communication Complex Cytoplasm DNA DNA Damage Detection Double-Stranded RNA Environment Event Gatekeeping Gene Expression Genomic Instability Genomics Goals Immune Immune response Immune system Immunotherapy Inflammasome Inflammatory Innate Immune Response Innate Immune System Interferon Type I Interferons Ligands Macrophage Malignant Neoplasms Malignant neoplasm of ovary Mechanical Stress Mechanics Mitosis Mitotic Modality Molecular Nuclear Envelope Nucleic Acids Pathway interactions Patients Pattern Recognition Pattern recognition receptor Phagocytes Pre-Clinical Model Process Program Research Project Grants Publishing RNA Reporting Research Research Personnel Signal Transduction Solid Neoplasm Testing Tissues Treatment outcome Viral Work adaptive immune response anti-tumor immune response arm cancer cell cancer immunotherapy checkpoint inhibition chromosome missegregation immune activation immune checkpoint blockade immunogenic improved in vivo mechanical force micronucleus multidisciplinary mutant neoplastic cell prevent rational design response sensor treatment response tumor tumor growth tumor microenvironment tumor-immune system interactions

项目摘要

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.

概括该计划项目赠款的总体目标是了解基本癌细胞基因组不稳定性与免疫之间通信的机制系统。研究人员对此P01的基础工作展示了多元的方式通过模式识别受体，将哪些基因组损伤异常被检测为“外来” 通常用于感知病毒核酸。我们小组的集体工作确定DNA损伤，组织结构的变化，有丝分裂错误和核包膜脆弱性用于泄露细胞的固有屏障，以防止内源性DNA和RNA 通过先天免疫模式识别传感器检测。这些事件严重影响肿瘤微环境促进或抑制肿瘤生长。为了实现我们的目标，我们有组建了三个项目，这些项目将与三个核心紧密合作，以解决有关的关键问题通过免疫反应检测肿瘤中基因组不稳定性。项目1调查 DNA损伤反应与内源性DNA的模式识别之间的关系细胞质中的RNA。项目2测试假设组织结构中的破坏和机械力导致染色体的错误分析和不稳定性。它描述了一种方法了解先天免疫系统对这种不稳定的认识。项目3调查体内对肿瘤内DNA损伤的反应，同时设计合理的方法以增强抗肿瘤免疫激活。这些多学科项目与哺乳动物人工的整合染色体和化学生物学核心将促进我们定义分子的主要目标免疫检测癌症基因组不稳定性的基础。