T-cell intrinsic mechanisms of resistance to PD-1 checkpoint blockade
T 细胞抵抗 PD-1 检查点阻断的内在机制
基本信息
- 批准号:10524151
- 负责人:
- 金额:$ 7.22万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AffectAffinityAntigensAntitumor ResponseAutomobile DrivingBindingBiological AssayCD8B1 geneCell AdhesionCell modelCellsCharacteristicsChromatographyCombined Modality TherapyDevelopmentEventGene ExpressionGene Expression ProfileGenetic TranscriptionGenomicsGoalsIn VitroIntrinsic factorKnowledgeLeadLinkMajor Histocompatibility ComplexMolecular ProfilingOptimum PopulationsPatient IsolatorsPatient SelectionPatientsPatternPeptidesPhosphorylationPopulationPropertyProteomicsReceptor SignalingResistanceRoleSamplingSelection for TreatmentsSignal TransductionSignaling ProteinStainsT cell responseT cell therapyT-Cell ActivationT-Cell ReceptorT-LymphocyteT-cell receptor repertoireTestingTumor AntigensTumor-Infiltrating LymphocytesWorkantigen-specific T cellsbasecancer immunotherapycancer therapycross reactivityeffective therapyexperimental studyhumanized mouseimmune checkpoint blockadeimprovedin vivomelanomamouse modelnew technologynovelpatient responsepotential biomarkerpredictive markerprogrammed cell death ligand 1programmed cell death protein 1receptorreceptor bindingresistance mechanismresponsetherapy resistanttranscriptomicstreatment optimizationtreatment responsetumorunnecessary treatment
项目摘要
PROJECT SUMMARY
Cancer immunotherapy has made great strides in recent years, yet improved approaches are required to
achieve more durable responses in a greater number of patients. Blockade of the inhibitory receptor
programmed-death 1 (PD-1) enables tumor-reactive T cells to effectively recognize and eliminate tumors in a
subset of responsive patients, but many patients are resistant to PD-1 blockade. To improve response rates, we
need to better understand the mechanisms that lead to therapeutic resistance. The overall goal of this project
is to understand the role of T cell–intrinsic factors that contribute to patient response versus resistance to
PD-1 blockade. We will identify signaling pathways and gene-expression patterns associated with blockade
response with a particular focus on the role of T-cell receptor (TCR) affinity. We hypothesize that the make-up
of TCR affinities of tumor-specific T cells affects tumor antigen recognition, activation signaling, and
downstream gene expression, thus contributing to patient response to therapy. Analysis of these parameters
in patient samples and mouse models of PD-1 blockade will allow us to identify T cell properties characteristic
of response to therapy. In our first aim we will isolate and quantify the TCR-binding properties of melanoma
antigen-specific T cells from PD-1 blockade–responsive and –resistant patients to determine how TCR affinity
profiles influence PD-1 blockade responses. In our second aim we will use proteomic and genomic analysis of
patient antigen-specific T cells to develop a global signature of PD-1 blockade response and resistance. In our
third aim we will use a panel of melanoma patient–derived TCRs with varying affinities for the same antigen
for in vitro and in vivo experiments to determine how TCR affinity influences response to PD-1 blockade.
Overall, we will determine the contribution of TCR affinities of melanoma-specific T cells to blockade
resistance and will provide evidence to support the targeting of specific T cells based on TCR affinity for
combination therapies and the selection of patients likely to respond to PD-1 blockade therapy based on TCR
affinity profiles.
项目摘要
近年来,癌症免疫疗法取得了长足的进步,但需要改进的方法
在更多的患者中获得更耐用的反应。抑制接收器的封锁
程序中性死亡1(PD-1)使肿瘤反应性T细胞有效地识别并消除了A中的肿瘤
反应敏感患者的子集,但许多患者对PD-1阻滞有抵抗力。为了提高响应率,我们
需要更好地了解导致治疗性抗性的机制。该项目的总体目标
是了解T细胞 - 互联母因素的作用,这些因素有助于患者的反应与对
PD-1封锁。我们将确定与封锁相关的信号通路和基因表达模式
特别关注T细胞受体(TCR)亲和力的作用的反应。我们假设化妆
肿瘤特异性T细胞的TCR亲和力影响肿瘤抗原识别,激活信号和
下游基因表达,从而有助于患者对治疗的反应。这些参数的分析
在PD-1封锁的患者样品和鼠标模型中,将使我们能够识别T细胞性质的特征
对治疗的反应。在我们的第一个目标中,我们将隔离和量化黑色素瘤的TCR结合特性
来自PD-1阻断响应和耐药的患者的抗原特异性T细胞,以确定TCR亲和力如何
轮廓会影响PD-1阻滞反应。在第二个目标中,我们将使用蛋白质组学和基因组分析
患者抗原特异性T细胞开发PD-1阻断反应和抗性的全局特征。在我们的
第三目的我们将使用一组黑色素瘤患者 - 衍生的TCR,具有相同抗原的亲和力不同
用于体外和体内实验,以确定TCR亲和力如何影响对PD-1阻滞的反应。
总体而言,我们将确定黑色素瘤特异性T细胞的TCR亲和力对封锁的贡献
阻力,并将提供证据以支持基于TCR亲和力的特定T细胞的靶向
组合疗法和基于TCR的PD-1封锁治疗可能反应的患者的选择
亲和力概况。
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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MICHELLE KROGSGAARD其他文献
MICHELLE KROGSGAARD的其他文献
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{{ truncateString('MICHELLE KROGSGAARD', 18)}}的其他基金
T-cell intrinsic mechanisms of resistance to PD-1 checkpoint blockade
T 细胞抵抗 PD-1 检查点阻断的内在机制
- 批准号:
10171108 - 财政年份:2020
- 资助金额:
$ 7.22万 - 项目类别:
T-cell intrinsic mechanisms of resistance to PD-1 checkpoint blockade
T 细胞抵抗 PD-1 检查点阻断的内在机制
- 批准号:
10369662 - 财政年份:2020
- 资助金额:
$ 7.22万 - 项目类别:
T-cell intrinsic mechanisms of resistance to PD-1 checkpoint blockade
T 细胞抵抗 PD-1 检查点阻断的内在机制
- 批准号:
10380381 - 财政年份:2020
- 资助金额:
$ 7.22万 - 项目类别:
T-cell intrinsic mechanisms of resistance to PD-1 checkpoint blockade
T 细胞抵抗 PD-1 检查点阻断的内在机制
- 批准号:
10609806 - 财政年份:2020
- 资助金额:
$ 7.22万 - 项目类别:
T-cell intrinsic mechanisms of resistance to PD-1 checkpoint blockade
T 细胞抵抗 PD-1 检查点阻断的内在机制
- 批准号:
10116340 - 财政年份:2020
- 资助金额:
$ 7.22万 - 项目类别:
Mechanisms of initiation of T-cell signaling by the TCR-CD3 complex
TCR-CD3 复合物启动 T 细胞信号传导的机制
- 批准号:
10193621 - 财政年份:2018
- 资助金额:
$ 7.22万 - 项目类别:
Mechanisms of impaired T-cell mechanosensing of melanoma antigens
黑色素瘤抗原 T 细胞机械感应受损的机制
- 批准号:
9899742 - 财政年份:2017
- 资助金额:
$ 7.22万 - 项目类别:
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