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 损伤性癌症疗法的功效取决于 (i) 内在 DNA 修复癌细胞的能力，以及（ii）对肿瘤发出的信号的免疫反应。了解 DNA 损伤与免疫之间通讯的分子基础因此，反应是癌症病因学和治疗的中心问题。我们报道称 DNA 损伤后有丝分裂进展允许 cGAS-STING 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 损伤诱导的细胞周期检查点的破坏与p53突变一起导致DNA和DNA的模式识别受体反应 RNA 传感器，包括 cGAS-STING 以及 MDA5 和 RIG-I/MAV 通路。我们的未发表的研究结果揭示了这些反应的额外复杂性。 NLRP9炎症小体染色体不稳定的癌细胞中的组装增加并对抗干扰素刺激回应。有趣的是，NLRP9 缺陷延迟了小鼠 Brca2 突变体的肿瘤形成与免疫逆转相称的高级别浆液性卵巢癌模型抑制性肿瘤微环境。这些发现可能解释 DNA 损伤如何激活或抑制抗肿瘤免疫反应。该提案将采用细胞、生化和体内方法来检验以下假设：染色体不稳定性激活二分炎症信号反应对肿瘤生长有不同的影响。这些机制对癌症的重要性免疫疗法将在评估全身抗肿瘤效果的同基因肿瘤模型中进行测试 DNA 损伤疗法和免疫检查点组合的免疫反应封锁。与项目 2 和 3 以及哺乳动物人工染色体的合作和化学生物学核心将有助于这些研究。