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:
- 金额:$ 35.68万
- 依托单位:
- 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:
- 关键词:AddressAffectAffinity ChromatographyAllelesArtificial Mammalian ChromosomesAuxinsBRCA2 geneBiochemicalBiologyBlack raceCancer BiologyCancer ControlCancer EtiologyCancer ModelCancer cell lineCell Cycle CheckpointCellsChemicalsChromosomal InstabilityCollaborationsCommunicationCoupledCytoplasmDNADNA DamageDNA RepairDNA Repair DisorderDevelopmentDimerizationDistant MetastasisDouble-Stranded RNAElementsFunctional disorderGene ExpressionGenomic InstabilityGrowthImmuneImmune responseImmunocompetentImmunosuppressionInflammasomeInflammatoryInnate Immune ResponseInterferonsInvestigationKnowledgeLigandsMacrophageMalignant NeoplasmsMalignant neoplasm of ovaryMediatingMitosisMitoticModelingMolecularMusMutationNucleic AcidsPARP inhibitionPathway interactionsPattern RecognitionPattern recognition receptorPreparationRNARNA HelicaseRNA libraryRegulationReportingSerousSignal TransductionStimulator of Interferon GenesSystemT-LymphocyteTP53 geneTestinganti-tumor immune responseantiviral immunityarmcancer cellcancer immunotherapycancer therapychromosome missegregationfluorescence imaginggenome integritygenotoxicityhomologous recombinationimmune activationimmune checkpoint blockadeimmunogenicin vivoirradiationmembermicronucleusmutantneoplastic cellnovel strategiesresponsesensortooltreatment responsetumortumor growthtumor microenvironmenttumor-immune system interactionsubiquitin-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unpublished findings reveal additional complexity to these responses.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.
总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Roger A Greenberg其他文献
Assembling a protective shield
组装一个防护盾
- DOI:
10.1038/s41556-018-0152-x - 发表时间:
2018-07-26 - 期刊:
- 影响因子:19.100
- 作者:
Roger A Greenberg - 通讯作者:
Roger A Greenberg
Roger A Greenberg的其他文献
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{{ truncateString('Roger A Greenberg', 18)}}的其他基金
Genome Instability Induced Anti-Tumor Immune Responses
基因组不稳定性诱导的抗肿瘤免疫反应
- 批准号:
10626281 - 财政年份:2023
- 资助金额:
$ 35.68万 - 项目类别:
Linking cancer cell metabolic reprogramming to the DNA repair mechanism
将癌细胞代谢重编程与 DNA 修复机制联系起来
- 批准号:
9040127 - 财政年份:2015
- 资助金额:
$ 35.68万 - 项目类别:
The RAP80-BRCC36 Deubiquitinating Complex in DNA Repair
DNA 修复中的 RAP80-BRCC36 去泛素化复合物
- 批准号:
9099237 - 财政年份:2015
- 资助金额:
$ 35.68万 - 项目类别:
Linking cancer cell metabolic reprogramming to the DNA repair mechanism
将癌细胞代谢重编程与 DNA 修复机制联系起来
- 批准号:
8879428 - 财政年份:2015
- 资助金额:
$ 35.68万 - 项目类别:
Roles of Chromatin Modification in BRCA1 Dependent DNA Repair
染色质修饰在 BRCA1 依赖性 DNA 修复中的作用
- 批准号:
8623113 - 财政年份:2013
- 资助金额:
$ 35.68万 - 项目类别:
DNA Double Strand Break Chromatin Alterations and Genome Integrity
DNA 双链断裂染色质改变和基因组完整性
- 批准号:
8665995 - 财政年份:2013
- 资助金额:
$ 35.68万 - 项目类别:
DNA Double Strand Break Chromatin Alterations and Genome Integrity
DNA 双链断裂染色质改变和基因组完整性
- 批准号:
8820272 - 财政年份:2013
- 资助金额:
$ 35.68万 - 项目类别:
DNA double-strand break chromatin alterations and genome integrity
DNA 双链断裂染色质改变和基因组完整性
- 批准号:
10799132 - 财政年份:2013
- 资助金额:
$ 35.68万 - 项目类别:
Roles of Chromatin Modification in BRCA1 Dependent DNA Repair
染色质修饰在 BRCA1 依赖性 DNA 修复中的作用
- 批准号:
8479097 - 财政年份:2013
- 资助金额:
$ 35.68万 - 项目类别:
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