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:10364056
- 负责人:
- 金额:$ 71.86万
- 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
- 来源:
- 关键词:AgonistAntiviral ResponseBiologyCell LineCellsClinical TrialsComplexDNADNA DamageDNA Repair EnzymesDNA-dependent protein kinaseDevelopmentEngraftmentGoalsHumanIRF3 geneImmuneImmune responseIn VitroInflammationInterferon Type IInterferonsLaboratory miceMalignant NeoplasmsMediatingMelanoma CellModalityModelingMusMyelogenousMyeloid CellsMyeloproliferative diseaseNonhomologous DNA End JoiningOutcomePathway interactionsPatientsPhosphorylationProductionSTING agonistsSignal TransductionSolid NeoplasmStimulusTestingTherapeuticTherapeutic EffectTumor AntigensTumor-infiltrating immune cellsantigen-specific T cellsantiviral immunitycancer immunotherapyeffector T cellhumanized mouseimmune checkpoint blockadein vivomelanomametastatic processmouse modelneoplastic cellnovelphosphoproteomicspreclinical evaluationrecruitrepairedresponsesensortumortumor microenvironment
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
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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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:
10553146 - 财政年份:2022
- 资助金额:
$ 71.86万 - 项目类别:
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