Tumor cell instrinsic DNA damage signaling to the immune response

肿瘤细胞内在 DNA 损伤向免疫反应发出信号

基本信息

批准号：
10626282
负责人：
Roger A Greenberg
金额：
$ 35.68万
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/10626282
关键词：
Address Affect Affinity Chromatography Alleles Artificial Mammalian Chromosomes Auxins BRCA2 gene Biochemical Biology Black race Cancer Biology Cancer Control Cancer Etiology Cancer Model Cancer cell line Cell Cycle Checkpoint Cells Chemicals Chromosomal Instability Collaborations Communication Coupled Cytoplasm DNA DNA Damage DNA Repair DNA Repair Disorder Development Dimerization Distant Metastasis Double-Stranded RNA Elements Functional disorder Gene Expression Genomic Instability Growth Immune Immune response Immunocompetent Immunosuppression Inflammasome Inflammatory Innate Immune Response Interferons Investigation Knowledge Ligands Macrophage Malignant Neoplasms Malignant neoplasm of ovary Mediating Mitosis Mitotic Modeling Molecular Mus Mutation Nucleic Acids PARP inhibition Pathway interactions Pattern Recognition Pattern recognition receptor Preparation RNA RNA Helicase RNA library Regulation Reporting Serous Signal Transduction Stimulator of Interferon Genes System T-Lymphocyte TP53 gene Testing anti-tumor immune response antiviral immunity arm cancer cell cancer immunotherapy cancer therapy chromosome missegregation fluorescence imaging genome integrity genotoxicity homologous recombination immune activation immune checkpoint blockade immunogenic in vivo irradiation member micronucleus mutant neoplastic cell novel strategies response sensor tool treatment response tumor tumor growth tumor microenvironment tumor-immune system interactions ubiquitin-protein ligase

项目摘要

Summary The efficacy of DNA damaging cancer therapies is determined by the (i) intrinsic DNA repair capacity of cancer cells, and (ii) immune responses to signals emanating from tumors. Understanding the molecular basis of communication between the DNA damage and immune responses is therefore a central issue to both cancer etiology and therapy. We reported that mitotic progression after DNA damage allows cGAS-STING dependent pattern recognition of DNA in micronuclei to initiate interferon-stimulated gene expression and T-cell dependent eradication of distant metastases. Disruption of DNA damage induced cell cycle checkpoints together with p53 mutation resulted in pattern recognition receptor responses by both DNA and RNA sensors, including the cGAS-STING and the MDA5 and RIG-I/MAVs pathways. Our unpublished findings reveal additional complexity to these responses. NLRP9 inflammasome assembly is increased in chromosomally instable cancer cells and opposes interferon stimulated responses. Interestingly, NLRP9 deficiency delayed tumor formation in a murine Brca2 mutant high grade serous ovarian cancer model commensurate with reversal of an immune suppressive tumor microenvironment. These findings potentially explain how DNA damage can either activate or suppress anti-tumor immune responses. This proposal will take cellular, biochemical, and in vivo approaches to test hypotheses that chromosome instability activates dichotomous inflammatory signaling responses that differentially affect tumor growth. The importance of these mechanisms to cancer immunotherapy will be tested in syngeneic tumor models that assess systemic anti-tumor immune responses to combinations of DNA damaging therapies and immune checkpoint blockade. Collaborations with Projects 2 and 3, and with the Mammalian Artificial Chromosome and Chemical Biology Cores will be instrumental to these studies.

概括 DNA破坏癌症疗法的功效由（i）固有的DNA修复确定癌细胞的能力，以及（ii）对从肿瘤产生的信号的免疫反应。了解DNA损伤与免疫之间通信的分子基础因此，反应是癌症病因和治疗的核心问题。我们报告了这一点 DNA损伤后有丝分裂进展允许CGAS插入依赖性模式识别微核中的DNA启动干扰素刺激的基因表达和T细胞依赖性根除远处转移。 DNA损伤引起的细胞周期检查点的破坏与p53突变一起导致DNA和 RNA传感器，包括CGAS-Sting和MDA5和RIG-I/MAVS途径。我们的未发表的发现揭示了这些反应的额外复杂性。 NLRP9炎性体在染色体上不稳定的癌细胞中增加组装，并反对干扰素刺激回答。有趣的是，NLRP9缺乏延迟肿瘤形成在鼠BRCA2突变体中高级浆液卵巢癌模型与免疫的逆转相称抑制性肿瘤微环境。这些发现可能解释了DNA损伤如何激活或抑制抗肿瘤免疫反应。该建议将采用细胞，生化和体内方法来检验假设的方法染色体不稳定性激活二分法炎症信号反应差异影响肿瘤生长。这些机制对癌症的重要性免疫疗法将在评估全身抗肿瘤的同性肿瘤模型中进行测试对DNA破坏疗法和免疫检查点的组合的免疫反应封锁。与项目2和3的合作，以及哺乳动物人造染色体化学生物学核心将对这些研究有用。