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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.

总结该计划项目补助金的总体目标是了解基本的癌细胞基因组不稳定性和免疫系统之间的潜在通讯机制系统研究人员对P01的基础工作表明，该基因组损伤被模式识别受体异常地检测为“外来的”，通常用于检测病毒核酸。我们团队的集体工作确定DNA损伤、组织结构变化、有丝分裂错误和核被膜脆弱性破坏了阻止内源性DNA和RNA 通过先天免疫模式识别传感器进行检测。这些事件严重影响肿瘤微环境以促进或抑制肿瘤生长。为了实现我们的目标，我们汇集了三个项目，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中的基因组不稳定性。项目1调查 DNA损伤反应与内源性DNA模式识别的关系，细胞质中的RNA。项目2测试了关于组织结构和组织结构如何被破坏的假设。机械力导致染色体错误分离和不稳定。它描述了一种方法来了解先天免疫系统对这种不稳定性的识别。项目3研究体内对肿瘤内DNA损伤的反应，同时设计合理的方法来增强抗肿瘤的能力。肿瘤免疫激活将这些多学科项目与哺乳动物人工染色体和化学生物学核心将推进我们的主要目标，癌症基因组不稳定性免疫检测的基础。