中性粒细胞衍生的蛋白酶消除 NSCLC 中的 IFNG 特征-猫眼课题宝

中性粒细胞衍生的蛋白酶消除 NSCLC 中的 IFNG 特征

批准号：

10717448

负责人：

A McGarry Houghton

金额：

$57.31万

依托单位：

FRED HUTCHINSON CANCER CENTER

依托单位国家：

美国

项目类别：

财政年份：

2023

资助国家：

美国

项目状态：

未结题

起止时间：

2023-07-07 至 2028-06-30

来源：

https://reporter.nih.gov/project-details/10717448

关键词：

Accounting Activated Lymphocyte Antibody Therapy Beds Biological Assay Bone Marrow CD8-Positive T-Lymphocytes CD8B1 gene CXC chemokine receptor 3 CXCL10 gene CXCL9 gene CXCR3 gene Cancer Etiology Cancer Patient Cathepsin G Cell surface Cells Cessation of life Chemotaxis Clinical Clinical Trials Cytoplasmic Granules Data Dendritic Cells Event Failure Feedback Fluorescent in Situ Hybridization Genes Human Immune Immune checkpoint inhibitor Immune response Immunohistochemistry Immunotherapy In Vitro Infiltration Interferon Type II Leukocyte Elastase Link Lung Neoplasms Lymphocyte Lymphocyte Function MMP8 gene MMP9 gene Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Measures Mediating Modeling Mus Myelogenous Myeloid-derived suppressor cells Neutrophil Collagenase Neutrophil Infiltration Non-Small-Cell Lung Carcinoma Outcome PD-1/PD-L1 Peptide Hydrolases Predictive Factor Process Production Property Protease Inhibitor Proteinase 3 Proteins Reporting Signal Transduction Site Source Surface System T cell infiltration T-Cell Activation T-Lymphocyte Testing Therapeutic Thinking Treatment outcome Tumor-associated macrophages Work anti-PD-1 anti-PD-L1 anti-PD-L1 therapy cell type checkpoint therapy chemokine chemokine receptor cohort cytokine exhaust immune checkpoint improved in vivo inhibitor mouse model mutant neoplastic cell neutrophil novel proteinase In recruit response success treatment response tumor tumor microenvironment

中文摘要

翻译

摘要尽管免疫检查点抑制物(ICI)治疗在临床上取得了巨大的成功，但只有~20%的非小细胞肺癌(NSCLC)患者对抗PD1/PDL1治疗有反应。预测的两个主要因素 ICI治疗的有利反应是出现IFNG信号和CD8+T细胞的证据向恶性肿瘤的侵袭。我们小组的研究表明，中性粒细胞渗入非小细胞肺肿瘤不显示IFNG信号，不显示CD8+向恶性肿瘤的浸润性，也不对ICI治疗有反应。我们解释这些观察结果的假设是肿瘤相关的中性粒细胞释放降解关键细胞因子(IFNG)、趋化因子(CXCL-9、-10、-11)和趋化因子的蛋白水解酶受体(CXCR3)，破坏IFNG介导的趋化梯度，促进T细胞渗透到肿瘤。拟议的研究将证明一些关键的中性粒细胞衍生的蛋白水解酶能够降解T细胞趋化因子和CXCR3，并鉴定产生的新的切割产物这些事件。这些蛋白分解事件的功能后果将在新的多细胞中得到证明。芯片内肿瘤系统和最先进的肺癌小鼠模型。最后，我们将联合使用荧光原位杂交(FISH)和多重免疫组织化学(M-IHC)板研究 CXCL9表达肿瘤细胞、CD8+CXCR3+T细胞与TAN的关系及检测这些措施对非小细胞肺癌患者ICI治疗结果的影响。

英文摘要

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.

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