Rewiring the myeloid cell response to adjuvants to improve tumor control
重新连接骨髓细胞对佐剂的反应以改善肿瘤控制
基本信息
- 批准号:10064141
- 负责人:
- 金额:$ 37.74万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-12-02 至 2024-11-30
- 项目状态:已结题
- 来源:
- 关键词:AdjuvantAnti-Inflammatory AgentsApoptoticBioinformaticsBiologicalBiological AssayCell MaturationCellsCessation of lifeChemotherapy and/or radiationClinicalCollectionCross PresentationCytotoxic ChemotherapyDataData SetDendritic CellsDose FractionationEnvironmentExposure toFailureGene Expression ProfileGenesGenetic TranscriptionHMGB1 geneHeat shock proteinsIRF3 geneImmuneImmunityImmunologic AdjuvantsImmunotherapyIn VitroInterferonsInterventionKnock-outLinkMalignant NeoplasmsMalignant neoplasm of pancreasMediatingMyelogenousMyeloid CellsNF-kappa BNecrosisOutcomePancreasPathologicPathologyPatient-Focused OutcomesPatientsPre-Clinical ModelProcessRNARadiation therapyRegulationResearch DesignResidual TumorsSamplingSignal TransductionStimulator of Interferon GenesT cell responseT-LymphocyteTestingTherapeuticToll-like receptorsTranscriptional RegulationTreatment FailureTumor BiologyTumor ImmunityTumor-associated macrophagescancer cellcancer typecheckpoint therapychemotherapyenvironmental enrichment for laboratory animalsextranuclear DNAimmune functionimmunogenicimprovedimproved outcomein vivomacrophagenovelpancreatic cancer modelpatient populationpatient responsepatient subsetspreventresponsesensorsuccesstumor
项目摘要
The critical preliminary data for this proposal is that contrary to the accepted dogma, following exposure to
endogenous immune adjuvants MyD88 delivers a negative signal to macrophages that limits tumor control by
radiation therapy. We demonstrate that in poorly immunogenic tumors, macrophages are rewired following
exposure to dying cancer cells such that they suppress multiple features of the tumor immune environment.
This includes the ability of T cells to control residual disease, and dendritic cell maturation. The aim of this
proposal is to understand the mechanisms by which this suppression occurs, identify the regulation of
macrophage suppression, and use this to identify patient populations that will respond poorly to current
therapies. We hypothesize that exposure to dying cells rewires macrophage signaling such that innate
activation of MyD88 suppresses local tumor immunity. The specific aims of this study are to 1: Test the
hypothesis that loss of MyD88 prevents NFKB driven-anti-inflammatory gene transcription and results in
increased IRF3 driven IFN transcription; 2: Test the hypothesis that signaling through Mertk-mediated ‘rewiring’
of macrophages changes the response to adjuvants limiting immune function in the tumor environment; and 3:
Test the hypothesis that MyD88 patterns of gene expression are linked to poor patient outcome. Our study
design incorporates CT-guided radiation therapy of multiple authentic pancreatic tumor models and using a
range of RT doses and fractionations. These are combined with unique knockouts and assays that allow us to
identify divergent myeloid responses in vitro and in vivo. Our analyses of clinical samples use high quality
bioinformatic approaches that allow us to evaluate effect of the tumor environment on the biological response
to innate adjuvants in patient samples.
这一建议的关键初步数据是,与公认的教条相反,在暴露于
项目成果
期刊论文数量(0)
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Michael James Gough其他文献
Michael James Gough的其他文献
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{{ truncateString('Michael James Gough', 18)}}的其他基金
DNASE1L3 regulation of anti-tumor immune responses following radiation therapy
DNASE1L3 对放射治疗后抗肿瘤免疫反应的调节
- 批准号:
10577698 - 财政年份:2023
- 资助金额:
$ 37.74万 - 项目类别:
Rewiring the myeloid cell response to adjuvants to improve tumor control
重新连接骨髓细胞对佐剂的反应以改善肿瘤控制
- 批准号:
10534119 - 财政年份:2019
- 资助金额:
$ 37.74万 - 项目类别:
Rewiring the myeloid cell response to adjuvants to improve tumor control
重新连接骨髓细胞对佐剂的反应以改善肿瘤控制
- 批准号:
10305679 - 财政年份:2019
- 资助金额:
$ 37.74万 - 项目类别:
High dose radiation therapy to direct immune responses to pancreatic cancer
高剂量放射治疗引导胰腺癌的免疫反应
- 批准号:
10411997 - 财政年份:2014
- 资助金额:
$ 37.74万 - 项目类别:
High dose radiation therapy to direct immune responses to pancreatic cancer
高剂量放射治疗引导胰腺癌的免疫反应
- 批准号:
10676741 - 财政年份:2014
- 资助金额:
$ 37.74万 - 项目类别:
High dose radiation therapy to direct immune responses to pancreatic cancer
高剂量放射治疗引导胰腺癌的免疫反应
- 批准号:
10160635 - 财政年份:2014
- 资助金额:
$ 37.74万 - 项目类别:
High dose radiation therapy to direct immune responses to pancreatic cancer
高剂量放射治疗引导胰腺癌的免疫反应
- 批准号:
8760163 - 财政年份:2014
- 资助金额:
$ 37.74万 - 项目类别:
High dose radiation therapy to direct immune responses to pancreatic cancer
高剂量放射治疗引导胰腺癌的免疫反应
- 批准号:
9815641 - 财政年份:2014
- 资助金额:
$ 37.74万 - 项目类别:
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