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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.

摘要