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

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 Our unpublished findings reveal additional complexity to these responses.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)
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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:
Admin Core A
管理核心A
  • 批准号:
    10626285
  • 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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