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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：
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
起止时间：
2023-07-07 至 2028-06-30
项目状态：
未结题

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

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.

抽象的尽管免疫检查点抑制剂 (ICI) 疗法在临床上取得了巨大成功，但只有约 20% 的非免疫检查点抑制剂 (ICI) 疗法在临床上取得了巨大成功。小细胞肺癌 (NSCLC) 患者对抗 PD1/PDL1 治疗有反应。预测的两大因素 ICI 治疗的良好治疗反应是 IFNG 特征的存在和 CD8+ T 细胞的证据浸润恶性肿瘤。我们小组的工作表明，中性粒细胞浸润非小细胞肺癌症不显示 IFNG 特征，不显示 CD8+ 浸润到恶性肿瘤中，也不显示对 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) 和趋化因子的蛋白酶受体（CXCR3）破坏 IFNG 介导的趋化梯度，促进 T 细胞浸润肿瘤。拟议的研究将证明许多关键的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 CXCR3 并鉴定出新的裂解产物这些事件。这些蛋白水解事件的功能后果将在新型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，我们将采用组合荧光原位杂交 (FISH) 和多重免疫组织化学 (M-IHC) 组合来研究 CXCL9表达肿瘤细胞、浸润CD8+CXCR3+T细胞和TAN之间的关系并确定这些措施对 NSCLC 患者 ICI 治疗结果的影响。