An innate immune checkpoint in cancer immunotherapy
癌症免疫治疗中的先天免疫检查点
基本信息
- 批准号:9447148
- 负责人:
- 金额:$ 46.82万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-03-01 至 2022-02-28
- 项目状态:已结题
- 来源:
- 关键词:AblationAcuteAntigen PresentationAntitumor ResponseApoptoticBreast Cancer ModelCancer ModelCell physiologyCellsColon CarcinomaComplementDataDefectDefense MechanismsDendritic CellsDendritic cell activationDevelopmentDiagnosisDisabled PersonsDiseaseDrug usageExcisionFDA approvedFailureFutureGeneticGenetically Engineered MouseGrowthHumanImmuneImmune checkpoint inhibitorImmune responseImmune signalingImmune systemImmunotherapeutic agentImmunotherapyIndividualInfiltrationInnate Immune SystemInterferon Type IInterferonsKnock-in MouseKnock-outKnockout MiceLeadLymphomaMC38MERTK geneMalignant NeoplasmsMeasuresMediatingModelingMolecularMusNamesNatural ImmunityPatientsPhagocytosisPhosphorylationPhosphotransferasesProcessProtein Tyrosine KinaseProteinsReceptor Protein-Tyrosine KinasesRegulationReportingResistanceSamplingSignal PathwaySignal TransductionSpecimenStainsT cell responseT-Cell ActivationT-LymphocyteTestingTherapeutic UsesTumor ImmunityTumor-Infiltrating LymphocytesTumor-associated macrophagesadaptive immunityanti-canceranti-tumor immune responsebasebeta cateninbiomarker panelcancer cellcancer geneticscancer immunotherapycancer preventioncancer therapycheckpoint therapycomparative efficacyfightinghuman diseaseimmune checkpointimmune checkpoint blockadeimprovedimproved functioninginhibitor/antagonistloss of functionmacrophagemelanomamolecular targeted therapiesmortalitymouse modelneutralizing antibodynovelpatient subsetspre-clinicalpredictive markerresponsesensorsmall moleculetargeted treatmenttumortumor growthweapons
项目摘要
Cancer immunotherapy attempts to boost the body’s own defense mechanism – the immune system – to kill
cancer cells and defeat cancer. Immunotherapy with T cell checkpoint inhibitors is promising to revolutionize
cancer therapy. However, a major limitation of these therapies is that they are effective in only a subset of
patients. Recent evidence suggests that enhanced T cell infiltration in the tumor is a predictive marker of
positive response to T cell checkpoint inhibitors. Thus, failure to respond to T cell checkpoint inhibitors may
correspond to a defect in the ability of the innate immune system to effectively engage adaptive anti-tumor
immune response. In mice, we have identified and disabled a novel immune checkpoint mechanism, a cellular
protein named MERTK, that is found in innate immune cells – the body’s first line of immune defense. MERTK
limits the extent to which innate immune cells can get activated, which in turn controls how much the overall
immune response would be. We have also detected the presence of MERTK in tumor-associated innate
immune cells in human samples. In mouse models of cancer, genetic ablation of Mertk results in dramatic
prevention of cancer growth. We propose to (i) use mouse models of cancers to investigate the mechanism/s
by which loss of MERTK function improves anti-tumor immunity, (ii) test if acute ablation of Mertk in
established tumors and the inactivation of its kinase activity are sufficient to overcome the failure to trigger anti-
tumor T cell responses and restrict tumor growth, and (iii) to investigate the association between MERTK
activation and the resistance to T cell checkpoint inhibitors in patients. Through these studies, we will better
understand how the immune system can fight cancer when the MERTK brake is removed, obtain proof-of-
concept for therapeutic use of drugs that would inhibit MERTK, and develop a predictive biomarker panel for
the identification of a subset of patients that are likely to respond to MERTK inhibitors. In summary, our
proposed studies can potentially identify a novel target for cancer immunotherapy that by itself, or in
combination with FDA-approved checkpoint inhibitors or molecular targeted therapies, could significantly
increase the percentage of patients that show objective response to anti-cancer therapy.
癌症免疫疗法试图增强人体自身的防御机制-免疫系统-杀死
癌细胞和战胜癌症。使用T细胞检查点抑制剂的免疫疗法有望彻底改变
癌症治疗然而,这些疗法的主要局限性在于它们仅在一部分患者中有效。
患者最近的证据表明,肿瘤中增强的T细胞浸润是肿瘤发生的预测标志物。
对T细胞检查点抑制剂有阳性反应。因此,对T细胞检查点抑制剂的应答失败可能
对应于先天免疫系统有效参与适应性抗肿瘤治疗的能力的缺陷
免疫反应在小鼠中,我们已经确定并禁用了一种新的免疫检查点机制,即细胞免疫检查点机制。
这种蛋白质名为MERTK,存在于先天免疫细胞中,是人体免疫防御的第一道防线。MERTK
限制了先天免疫细胞被激活的程度,这反过来又控制了整体免疫细胞的数量。
免疫反应是什么。我们还检测到MERTK在肿瘤相关先天性巨噬细胞中的存在。
人体样本中的免疫细胞在小鼠癌症模型中,Mertk的基因切除导致了显着的
预防癌症生长。我们建议(i)使用小鼠癌症模型来研究其机制,
MERTK功能的丧失通过其改善抗肿瘤免疫,(ii)测试是否急性消融MERTK,
建立的肿瘤和其激酶活性的失活足以克服触发抗肿瘤的失败,
肿瘤T细胞应答并限制肿瘤生长,以及(iii)研究MERTK与肿瘤细胞增殖和肿瘤细胞增殖之间的关联。
活化和患者对T细胞检查点抑制剂的抗性。通过这些研究,我们将更好地
了解当MERTK制动器被移除时,免疫系统如何对抗癌症,
治疗性使用药物的概念,将抑制MERTK,并开发一个预测性生物标志物面板,
确定可能对MERTK抑制剂有应答的患者子集。总之,我们的
提出的研究可以潜在地确定癌症免疫治疗的新靶点,
与FDA批准的检查点抑制剂或分子靶向治疗联合使用,
增加对抗癌治疗显示出客观反应的患者的百分比。
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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Sourav Ghosh其他文献
Sourav Ghosh的其他文献
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{{ truncateString('Sourav Ghosh', 18)}}的其他基金
Augmenting AXL and MERTK function to restrain cognitive decline and improve health span in mouse models of Alzheimer's Disease
增强 AXL 和 MERTK 功能以抑制阿尔茨海默氏病小鼠模型的认知衰退并改善健康寿命
- 批准号:
10662677 - 财政年份:2023
- 资助金额:
$ 46.82万 - 项目类别:
Naïve T cell archetypes and anti-tumor immunity
幼稚 T 细胞原型和抗肿瘤免疫
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10741153 - 财政年份:2023
- 资助金额:
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Sex-Specific Single Cell Expression Profiles, Genetic Risk and Drug Responsiveness in Alzheimer's Disease
阿尔茨海默病的性别特异性单细胞表达谱、遗传风险和药物反应
- 批准号:
10467589 - 财政年份:2021
- 资助金额:
$ 46.82万 - 项目类别:
An innate immune checkpoint in cancer immunotherapy
癌症免疫治疗中的先天免疫检查点
- 批准号:
10286793 - 财政年份:2017
- 资助金额:
$ 46.82万 - 项目类别:
Apical-basal polarity signaling in glioblastoma
胶质母细胞瘤中的顶端-基底极性信号传导
- 批准号:
8657870 - 财政年份:2010
- 资助金额:
$ 46.82万 - 项目类别:
Apical-basal polarity signaling in glioblastoma
胶质母细胞瘤中的顶端-基底极性信号传导
- 批准号:
8461275 - 财政年份:2010
- 资助金额:
$ 46.82万 - 项目类别:
Apical-basal polarity signaling in glioblastoma
胶质母细胞瘤中的顶底极性信号传导
- 批准号:
8817344 - 财政年份:2010
- 资助金额:
$ 46.82万 - 项目类别:
Apical-basal polarity signaling in glioblastoma
胶质母细胞瘤中的顶底极性信号传导
- 批准号:
8915298 - 财政年份:2010
- 资助金额:
$ 46.82万 - 项目类别:
Apical-basal polarity signaling in glioblastoma
胶质母细胞瘤中的顶端-基底极性信号传导
- 批准号:
8649817 - 财政年份:2010
- 资助金额:
$ 46.82万 - 项目类别:
Apical-basal polarity signaling in glioblastoma
胶质母细胞瘤中的顶端-基底极性信号传导
- 批准号:
8527897 - 财政年份:2010
- 资助金额:
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