Activation of the DNA-PK-dependent antiviral response as a novel cancer immunotherapy

激活 DNA-PK 依赖性抗病毒反应作为一种新型癌症免疫疗法

基本信息

  • 批准号:
    10553146
  • 负责人:
  • 金额:
    $ 68.25万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-01-20 至 2026-12-31
  • 项目状态:
    未结题

项目摘要

Project Summary/Abstract Checkpoint blockade has revolutionized the field of cancer immunotherapy treatment, but many tumors remain unresponsive due to lack of effector T cell infiltration and activation in the tumor microenvironment. Innate immune priming of these “cold” tumors has emerged as a therapeutic strategy for increasing the efficacy of checkpoint blockade through stimulated type I interferon (IFN) production and downstream adaptive response. Recent efforts and ongoing clinical trials have focused on activation of the STING-dependent antiviral pathway to promote IFN production in the tumor microenvironment. However, many tumors downregulate STING signaling, and the therapeutic effects of STING agonists are thought to be mediated by their effects on tumor- infiltrating host myeloid cells. Our lab recently discovered that the DNA damage sensor DNA-PK triggers a STING-independent DNA sensing pathway (SIDSP) in human cells that potently activates IFN production in response to foreign DNA. We have developed synthetic superagonists of DNA-PK-dependent antiviral immunity that trigger potent antiviral responses in human melanoma cells that are unresponsive to STING agonists. We hypothesize that activation of the SIDSP within tumor cells will provide a unique signal to enhance inflammation within tumors and will stimulate potent immune responses. The goal of this proposal is to assess DNA-PK-SIDSP activation as a therapeutic strategy in human cancer. We will determine how DNA-PK directs distinct outcomes to DNA damage versus foreign DNA, and we will evaluate the therapeutic potential of triggering the DNA-PK-SIDSP in human tumors, in vitro and in vivo using cutting edge humanized mouse models. Our studies will uncover fundamental new aspects of the biology of the SIDSP, together with the first pre-clinical evaluation of DNA-PK activation as a novel cancer immunotherapy.
项目总结/文摘

项目成果

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ANTHONY RONGVAUX其他文献

ANTHONY RONGVAUX的其他文献

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{{ truncateString('ANTHONY RONGVAUX', 18)}}的其他基金

Activation of the DNA-PK-dependent antiviral response as a novel cancer immunotherapy
激活 DNA-PK 依赖性抗病毒反应作为一种新型癌症免疫疗法
  • 批准号:
    10364056
  • 财政年份:
    2022
  • 资助金额:
    $ 68.25万
  • 项目类别:
Targeting macrophages in metastatic cancer
靶向转移性癌症中的巨噬细胞
  • 批准号:
    10334469
  • 财政年份:
    2019
  • 资助金额:
    $ 68.25万
  • 项目类别:
Targeting macrophages in metastatic cancer
靶向转移性癌症中的巨噬细胞
  • 批准号:
    10582536
  • 财政年份:
    2019
  • 资助金额:
    $ 68.25万
  • 项目类别:
Targeting macrophages in metastatic cancer
靶向转移性癌症中的巨噬细胞
  • 批准号:
    9762498
  • 财政年份:
    2019
  • 资助金额:
    $ 68.25万
  • 项目类别:
Targeting macrophages in metastatic cancer
靶向转移性癌症中的巨噬细胞
  • 批准号:
    10604537
  • 财政年份:
    2019
  • 资助金额:
    $ 68.25万
  • 项目类别:
Targeting macrophages in metastatic cancer
靶向转移性癌症中的巨噬细胞
  • 批准号:
    10080719
  • 财政年份:
    2019
  • 资助金额:
    $ 68.25万
  • 项目类别:

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