Activation of the DNA-PK-dependent antiviral response as a novel cancer immunotherapy
Activation of the DNA-PK-dependent antiviral response as a novel cancer immunotherapy
批准号:
10553146
负责人:
ANTHONY RONGVAUX
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
项目状态:
未结题
起止时间:
2022-01-20 至 2026-12-31
关键词:
Antiviral ResponseBiologyCell LineCellsClinical TrialsComplexDNADNA DamageDNA Repair EnzymesDNA-dependent protein kinaseDevelopmentEngraftmentGoalsHumanIRF3 geneImmuneImmune responseIn VitroInfiltrationInflammationInterferon Type IInterferonsLaboratory miceMalignant NeoplasmsMediatingMelanoma CellModalityModelingMusMyelogenousMyeloid CellsMyeloproliferative diseaseNonhomologous DNA End JoiningOutcomePathway interactionsPatientsPhosphorylationProductionSTING agonistsSignal TransductionSolid NeoplasmStimulusSting InjuryT cell infiltrationTestingTherapeuticTherapeutic EffectTumor AntigensViralantigen-specific T cellsantiviral immunitycancer immunotherapyeffector T cellhumanized mouseimmune checkpoint blockadein vivomelanomametastatic processmouse modelneoplastic cellnovelphosphoproteomicspreclinical evaluationrecruitrepairedresponsesensortumortumor microenvironment
中文摘要
项目摘要/摘要
检查站封锁彻底改变了癌症免疫治疗领域,但许多肿瘤仍然存在
由于肿瘤微环境中缺乏效应性T细胞的渗透和激活而无反应。先天的
免疫启动这些“冷”肿瘤已经成为一种治疗策略,以提高疗效
通过刺激I型干扰素的产生和下游适应性反应实现检查点阻断。
最近的努力和正在进行的临床试验都集中在激活依赖刺痛的抗病毒途径上。
促进肿瘤微环境中干扰素的产生。然而,许多肿瘤下调了刺痛的表达。
信号转导,而STING激动剂的治疗作用被认为是通过它们对肿瘤的影响而介导的。
渗入宿主髓系细胞。
我们的实验室最近发现,DNA损伤传感器DNA-PK触发了一种非刺激性DNA
人类细胞中的感应通路(SIDSP),它能有效地激活干扰素的产生,以响应外来DNA。
我们已经开发出依赖DNA-PK的抗病毒免疫的合成超级激动剂,可以触发强大的
人类黑色素瘤细胞对刺痛激动剂无反应的抗病毒反应。我们假设
激活肿瘤细胞内的SIDSP将提供一个独特的信号来增强肿瘤内的炎症
并将激发强大的免疫反应。
这项建议的目标是评估DNA-PK-SIDSP激活作为人类治疗策略
癌症。我们将确定DNA-PK如何对DNA损伤和外来DNA造成不同的结果,我们
将评估在体外和体内触发DNA-PK-SIDSP对人类肿瘤的治疗潜力
使用尖端的人性化老鼠模型。我们的研究将揭示生物学的基本新方面
以及首次对DNA-PK激活作为一种新癌症的临床前评估
免疫疗法。
英文摘要
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.
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会议论文
Activation of the DNA-PK-dependent antiviral response as a novel cancer immunotherapy
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批准号:10364056
-
项目类别:
-
资助金额:$71.86万
-
财政年份:2022
-
负责人:ANTHONY RONGVAUX
-
依托单位:
Targeting macrophages in metastatic cancer
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批准号:10334469
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项目类别:
-
资助金额:$6.5万
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财政年份:2019
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负责人:ANTHONY RONGVAUX
-
依托单位:
Targeting macrophages in metastatic cancer
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批准号:10582536
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项目类别:
-
资助金额:$41.57万
-
财政年份:2019
-
负责人:ANTHONY RONGVAUX
-
依托单位:
Targeting macrophages in metastatic cancer
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批准号:9762498
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项目类别:
-
资助金额:$44.55万
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财政年份:2019
-
负责人:ANTHONY RONGVAUX
-
依托单位:
Targeting macrophages in metastatic cancer
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批准号:10604537
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项目类别:
-
资助金额:$35.92万
-
财政年份:2019
-
负责人:ANTHONY RONGVAUX
-
依托单位:
Targeting macrophages in metastatic cancer
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批准号:10080719
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项目类别:
-
资助金额:$45.55万
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财政年份:2019
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负责人:ANTHONY RONGVAUX
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依托单位:
国内基金
海外基金
Journal of Integrative Plant Biology
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批准号:31024801
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项目类别:专项基金项目
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资助金额:24.0万元
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批准年份:2010
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负责人:贺萍
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依托单位: