E3 ligase mediated control of Foxp3 expression and immune suppression-mechanisms and potential as immunotherapeutic target
E3连接酶介导的Foxp3表达和免疫抑制机制的控制以及作为免疫治疗靶点的潜力
基本信息
- 批准号:10331033
- 负责人:
- 金额:$ 37.91万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-02-01 至 2023-01-31
- 项目状态:已结题
- 来源:
- 关键词:AchievementAdvanced Malignant NeoplasmAffectAnti-Inflammatory AgentsAutoimmuneAutoimmune DiseasesAutoimmunityBiochemicalBiologyCancer PatientCancer VaccinesCell CompartmentationCell NucleusCell physiologyCellsCharacteristicsChemicalsCytoplasmDetectionDevelopmentDiseaseDisease modelDissectionDown-RegulationDrug ScreeningElementsEnzymesFOXP3 geneGenerationsGeneticHomeostasisHost DefenseHumanIL2RA geneImmuneImmune mediated destructionImmune responseImmune systemImmunomodulatorsImmunosuppressionImmunotherapeutic agentImmunotherapyInfectionInflammatoryInterruptionInterventionInvestigational TherapiesKnock-outLeadLeukocytesLigaseLipopolysaccharidesMalignant NeoplasmsMalignant neoplasm of ovaryMediatingModelingModificationMolecularMusMutateOutcomePathologyPathway interactionsPharmacologyPhenotypePhosphorylationPhosphotransferasesPhysiologicalPlayPolyubiquitinationPost-Translational Protein ProcessingPost-Translational RegulationProcessProteinsRegulationRegulatory PathwayRegulatory T-LymphocyteReporterResearchRiskRoleRoswell Park Cancer InstituteSignal PathwaySignal TransductionSiteSmall Interfering RNAStimulusStressT-LymphocyteT-Lymphocyte SubsetsTestingTherapeuticTissuesTransgenic MiceTumor EscapeTumor ImmunityUbiquitinWorkanti-canceranti-tumor immune responsebasecancer immunotherapycell bankcytokineefficacy testingexperimental studyfitnessglycogen synthase kinase 3 beta inhibitorimmune activationimmunoregulationin vitro Modelin vivoinflammatory milieuinhibitorknock-downmelanomaneoplasm immunotherapyneoplastic cellnoveloverexpressionpreventresponserestraintscreeningside effecttargeted agenttranscription factortumortumor eradicationtumor growthtumor microenvironmentubiquitin-protein ligasevaccine efficacy
项目摘要
Project Summary
Tumor cells exploit mechanisms of immune regulation to evade detection and eradication by host defenses.
Foxp3+CD4+CD25+ regulatory T cell (Treg)-mediated immune suppression is crucial for immune evasion by
tumor cells and an obstacle for successful tumor immunotherapy. Hence, the ability to disrupt Treg function is
of major therapeutic significance. Recent work by us and others revealed that the key Treg transcription factor,
Foxp3 is subject to polyubiquitination-dependent posttranslational regulation. Particularly, we found the E3
ubiquitin ligase Stub1, which is induced in response to a range of stress signals, facilitates the degradation of
Foxp3 providing a potential target for dynamic modulation of Treg suppression. In the current proposal, we are
seeking to: 1) Dissect molecular signaling pathways involved in Stub1 expression and its post-translational
modification; 2) Understand the consequences of physiological Stub1 induction and genetic deletion for Treg
cell homeostasis, differentiation and function; and 3) Test pharmacological activators of Foxp3 ubquitination as
novel immunotherapic strategies to undermine immune suppression in the cancer setting. These studies will
expand our understanding of the mechanisms behind posttranslational Foxp3 regulation. Specifically, we will
further explore pathways determining Stub1 activity and expression, including the previously unappreciated
phosphorylation of the ligase by the kinase GS3Kβ. To this end, we will utilize biochemical approaches and
well-characterized models of in vitro and in vivo Treg function to establish the consequences of ablating these
pathways. Furthermore, pharmacological modifiers of the Stub1/Ubiquitin-dependent pathway for Foxp3
degradation (identified in a drug screen and previous studies) will be tested for efficacy as breakers of immune
suppression - a major obstacle for anti-cancer immunotherapy. This vetting will be carried out in an aggressive
murine melanoma model (in vivo) as well as in ex vivo studies of human leukocytes obtained from healthy
donors and advanced cancer patients. In so doing we will determine the potential therapeutic application of
modulating Stub1 activity to boost anti-tumor immunity. Our experiments may reveal novel modes of regulating
Stub1 activity and Foxp3 protein downregulation. Detailed assessment of physiological Stub1 induction and its
impact on Foxp3 and Treg function is predicted to demonstrate a potent therapeutic application. Use of Stub1-
activators in combination with proven checkpoint targeting agents may yield even better anti-tumor efficacy.
项目摘要
肿瘤细胞利用免疫调节机制来逃避宿主防御的检测和根除。
Foxp3+CD4+CD25+调节性T细胞(Treg)介导的免疫抑制是免疫逃避的关键,通过
肿瘤细胞和肿瘤免疫治疗成功的障碍。因此,中断Treg功能的能力是
具有重要的治疗意义。我们和其他人最近的研究表明,关键的Treg转录因子,
Foxp3受依赖于多泛素化的翻译后调控。特别是,我们发现了E3
泛素连接酶Stub1是在一系列应激信号的作用下诱导的,它促进了细胞的降解
Foxp3为Treg抑制的动态调控提供了一个潜在的靶点。在目前的提案中,我们是
试图:1)剖析参与Stub1表达及其翻译后的分子信号通路
修改;2)了解Treg的生理性Stub1诱导和基因缺失的后果
细胞内稳态、分化和功能;3)检测Foxp3泛素化的药理激活剂
新的免疫疗法策略,以破坏癌症环境中的免疫抑制。这些研究将
扩大我们对翻译后Foxp3调控机制的理解。具体来说,我们将
进一步探索确定Stub1活性和表达的途径,包括以前未被识别的
GS3Kβ使连接酶磷酸化。为此,我们将利用生化方法和
体外和体内Treg功能的良好表征模型以建立消融这些细胞的后果
小路。此外,Foxp3的Stub1/泛素依赖途径的药理修饰物
降解物(在药物筛选和以前的研究中确定)将作为免疫破坏者的有效性进行测试
抑制--抗癌免疫治疗的主要障碍。这项审查将以积极的方式进行
小鼠黑色素瘤模型(体内)以及对健康人白细胞的体外研究
捐赠者和晚期癌症患者。在此过程中,我们将确定其潜在的治疗应用
调节Stub1活性以增强抗肿瘤免疫。我们的实验可能会揭示新的调节模式
Stub1活性和Foxp3蛋白下调。生理性Stub1诱导的详细评估及其
对Foxp3和Treg功能的影响被预测为一种有效的治疗应用。使用Stub1-
激活剂与已证实的检查点靶向药物相结合,可能会产生更好的抗肿瘤效果。
项目成果
期刊论文数量(1)
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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DREW M. PARDOLL其他文献
DREW M. PARDOLL的其他文献
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{{ truncateString('DREW M. PARDOLL', 18)}}的其他基金
Role of YAP in Treg Function and YAP Targeting for Cancer Immunotherapy
YAP 在 Treg 功能中的作用和 YAP 靶向癌症免疫治疗
- 批准号:
10547779 - 财政年份:2018
- 资助金额:
$ 37.91万 - 项目类别:
Role of YAP in Treg Function and YAP Targeting for Cancer Immunotherapy
YAP 在 Treg 功能中的作用和 YAP 靶向癌症免疫治疗
- 批准号:
10330418 - 财政年份:2018
- 资助金额:
$ 37.91万 - 项目类别:
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EOS 在调节性 T 细胞生物学中的作用。
- 批准号:
8490291 - 财政年份:2010
- 资助金额:
$ 37.91万 - 项目类别:
Mechanisms of TH17 Inflammation-Induced Colon Carcihogenesis
TH17炎症诱导的结肠癌发生机制
- 批准号:
8657874 - 财政年份:2010
- 资助金额:
$ 37.91万 - 项目类别:
The Role of EOS in Regulatory T-cell Biology.
EOS 在调节性 T 细胞生物学中的作用。
- 批准号:
8683077 - 财政年份:2010
- 资助金额:
$ 37.91万 - 项目类别:
Mechanisms of TH17 Inflammation-Induced Colon Carcihogenesis
TH17炎症诱导的结肠癌发生机制
- 批准号:
8105255 - 财政年份:2010
- 资助金额:
$ 37.91万 - 项目类别:
Enterotoxigenic Bacteroides fragilis: A bacterial promoter of colon oncogenesis
产肠毒素脆弱拟杆菌:结肠癌发生的细菌启动子
- 批准号:
8707985 - 财政年份:2010
- 资助金额:
$ 37.91万 - 项目类别:
PD-1/PD-L1 modulation in cancer therapy
癌症治疗中的 PD-1/PD-L1 调节
- 批准号:
10355495 - 财政年份:2010
- 资助金额:
$ 37.91万 - 项目类别:
Enterotoxigenic Bacteroides fragilis: A bacterial promoter of colon oncogenesis
产肠毒素脆弱拟杆菌:结肠癌发生的细菌启动子
- 批准号:
8137121 - 财政年份:2010
- 资助金额:
$ 37.91万 - 项目类别:














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