Neutrophil derived proteinases abolish the IFNG signature in NSCLC
中性粒细胞衍生的蛋白酶消除 NSCLC 中的 IFNG 特征
基本信息
- 批准号:10717448
- 负责人:
- 金额:$ 57.31万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-07 至 2028-06-30
- 项目状态:未结题
- 来源:
- 关键词:AccountingActivated LymphocyteAntibody TherapyBedsBiological AssayBone MarrowCD8-Positive T-LymphocytesCD8B1 geneCXC chemokine receptor 3CXCL10 geneCXCL9 geneCXCR3 geneCancer EtiologyCancer PatientCathepsin GCell surfaceCellsCessation of lifeChemotaxisClinicalClinical TrialsCytoplasmic GranulesDataDendritic CellsEventFailureFeedbackFluorescent in Situ HybridizationGenesHumanImmuneImmune checkpoint inhibitorImmune responseImmunohistochemistryImmunotherapyIn VitroInfiltrationInterferon Type IILeukocyte ElastaseLinkLung NeoplasmsLymphocyteLymphocyte FunctionMMP8 geneMMP9 geneMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of lungMeasuresMediatingModelingMusMyelogenousMyeloid-derived suppressor cellsNeutrophil CollagenaseNeutrophil InfiltrationNon-Small-Cell Lung CarcinomaOutcomePD-1/PD-L1Peptide HydrolasesPredictive FactorProcessProductionPropertyProtease InhibitorProteinase 3ProteinsReportingSignal TransductionSiteSourceSurfaceSystemT cell infiltrationT-Cell ActivationT-LymphocyteTestingTherapeuticThinkingTreatment outcomeTumor-associated macrophagesWorkanti-PD-1anti-PD-L1anti-PD-L1 therapycell typecheckpoint therapychemokinechemokine receptorcohortcytokineexhaustimmune checkpointimprovedin vivoinhibitormouse modelmutantneoplastic cellneutrophilnovelproteinase Inrecruitresponsesuccesstreatment responsetumortumor microenvironment
项目摘要
ABSTRACT
Although immune checkpoint inhibitor (ICI) therapy has been a tremendous clinical success, just ~20% of non-
small cell lung cancer (NSCLC) patients respond to anti-PD1/PDL1 therapy. The two major factors predictive of
favorable treatment response to ICI therapy are the presence of the IFNG signature and evidence of CD8+ T cell
infiltration into malignant tumor. Work from our group has shown that neutrophil infiltrated non-small cell lung
cancers do not display the IFNG signature, do not display CD8+ infiltration into malignant tumor, and do not
respond to ICI treatment. Our hypothesis to explain these observations is that tumor-associated neutrophils
release proteinases that degrade key cytokines (IFNG), chemokines (CXCL-9, -10, -11) and a chemokine
receptor (CXCR3) that destroys the IFNG mediated chemotactic gradient that facilitates T cell infiltration into
tumors. The proposed studies will demonstrate that a number of key neutrophil-derived proteinases are capable
of degrading T cell recruiting chemokines and CXCR3 and identify the novel cleavage products resulting from
these events. The functional consequences of these proteolytic events will be demonstrated in novel multicellular
tumor-in-chip systems and in state-of-the art mouse models of lung cancer. Lastly, we will employ a combined
fluorescent in-situ hybridization (FISH) and multiplexed immunohistochemistry (M-IHC) panel to study the
relationship between CXCL9 expressing tumor cells, infiltrating CD8+CXCR3+ T cells, and TAN and determine
the impact that these measures have on ICI treatment outcomes in NSCLC patients.
摘要
虽然免疫检查点抑制剂(ICI)治疗已经取得了巨大的临床成功,但只有约20%的非免疫检查点抑制剂治疗。
小细胞肺癌(NSCLC)患者对抗PD 1/PDL 1治疗有反应。两个主要的预测因素
对ICI治疗有利的治疗反应是IFNG标记的存在和CD 8 + T细胞的证据,
恶性肿瘤浸润。我们小组的工作表明,中性粒细胞浸润的非小细胞肺
癌症不显示IFNG标记,不显示CD 8+浸润到恶性肿瘤中,并且不
对ICI治疗有反应。我们解释这些观察结果的假设是,肿瘤相关中性粒细胞
释放降解关键细胞因子(IFNG)、趋化因子(CXCL-9、-10、-11)和趋化因子的蛋白酶
受体(CXCR 3),破坏IFNG介导的趋化梯度,促进T细胞浸润到
肿瘤的拟议的研究将证明,一些关键的嗜中性粒细胞衍生的蛋白酶能够
降解T细胞募集趋化因子和CXCR 3,并确定由
这些事件。这些蛋白水解事件的功能后果将在新的多细胞生物学中得到证实。
肿瘤芯片系统和最先进的肺癌小鼠模型。最后,我们将使用一个组合
荧光原位杂交(FISH)和多重免疫组织化学(M-IHC)面板,以研究
表达CXCL 9的肿瘤细胞、浸润性CD 8 + CXCR 3 + T细胞和TAN之间的关系,
这些措施对NSCLC患者ICI治疗结局的影响。
项目成果
期刊论文数量(0)
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A McGarry Houghton其他文献
A McGarry Houghton的其他文献
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{{ truncateString('A McGarry Houghton', 18)}}的其他基金
Anxa2 drives the function of immune suppressive neutrophils in lung cancer
Anxa2 驱动肺癌中免疫抑制性中性粒细胞的功能
- 批准号:
10310981 - 财政年份:2021
- 资助金额:
$ 57.31万 - 项目类别:
A Quantitative PET/CT Research Resource for Co-Clinical Imaging of Lung Cancer Therapies
用于肺癌治疗联合临床成像的定量 PET/CT 研究资源
- 批准号:
10301566 - 财政年份:2021
- 资助金额:
$ 57.31万 - 项目类别:
A Quantitative PET/CT Research Resource for Co-Clinical Imaging of Lung Cancer Therapies
用于肺癌治疗联合临床成像的定量 PET/CT 研究资源
- 批准号:
10700944 - 财政年份:2021
- 资助金额:
$ 57.31万 - 项目类别:
Liquid biopsy of the lung to profile lung cancer
肺部液体活检以分析肺癌
- 批准号:
10053675 - 财政年份:2020
- 资助金额:
$ 57.31万 - 项目类别:
Liquid biopsy of the lung to profile lung cancer
肺部液体活检以分析肺癌
- 批准号:
10259860 - 财政年份:2020
- 资助金额:
$ 57.31万 - 项目类别:
Liquid biopsy of the lung to profile lung cancer
肺部液体活检以分析肺癌
- 批准号:
10472743 - 财政年份:2020
- 资助金额:
$ 57.31万 - 项目类别:
Liquid biopsy of the lung to profile lung cancer
肺部液体活检以分析肺癌
- 批准号:
10601449 - 财政年份:2020
- 资助金额:
$ 57.31万 - 项目类别:
Project 1: Targeting the Neutrophil Lineage To Enhance Immune Checkpoint Inhibitor Efficacy in NSCLC
项目1:靶向中性粒细胞谱系以增强非小细胞肺癌中免疫检查点抑制剂的功效
- 批准号:
10174872 - 财政年份:2019
- 资助金额:
$ 57.31万 - 项目类别:
Tumor-specific autoantibodies for SCLC early detection
用于 SCLC 早期检测的肿瘤特异性自身抗体
- 批准号:
10299616 - 财政年份:2019
- 资助金额:
$ 57.31万 - 项目类别: