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Identifying the role of Ntrk1 in immunosuppression in Kras/p53 mutant lung cancer

鉴定 Ntrk1 在 Kras/p53 突变肺癌免疫抑制中的作用

基本信息

批准号：
9906415
负责人：
Jessica Konen
金额：
$ 7.01万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-09 至 2022-12-08
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9906415
关键词：
Address Adenosine Bar Codes Blocking Antibodies CD8-Positive T-Lymphocytes Cancer Etiology Cancer Patient Cell Communication Cell Line Cell Survival Cell physiology Cells Cessation of life Chimeric Proteins Clinic Clinical Clinical Research Collection Combined Modality Therapy Data Dependence Development Dropout Drug Combinations Drug Targeting Epithelial Epithelium FDA approved Flow Cytometry Functional disorder Genes Genetic Genetic Engineering Goals Growth Human Image Immune Immune System Diseases Immune checkpoint inhibitor Immune system Immunocompetent Immunomodulators Immunosuppression Immunotherapy Implant Inflammatory Interleukin-10 KRAS2 gene Libraries Lung Neoplasms Lung diseases MAP Kinase Gene Malignant Neoplasms Malignant neoplasm of lung Mesenchymal Mesenchymal Cell Neoplasm Messenger RNA Minority Mus Mutation Neoplasm Metastasis Neurons Non-Small-Cell Lung Carcinoma Outcome PD-1 blockade PD-1 inhibitors PD-1/PD-L1 PDL1 inhibitors Pathway interactions Patient-Focused Outcomes Patients Phenotype Phosphotransferases Population Pre-Clinical Model Protein Tyrosine Kinase Proteins Proto-Oncogene Proteins c-akt Receptor Protein-Tyrosine Kinases Resistance Resistance development Role Signal Transduction Solid Neoplasm Splenocyte Survival Rate T-Lymphocyte TP53 gene Testing Therapeutic Time Tissue Sample Transcript Transcriptional Activation United States Up-Regulation Woman Work anti-PD1 antibodies base cancer cell cancer immunotherapeutics cancer type checkpoint inhibition clinical application clinically relevant cytokine exhaust exhaustion genetic signature genomic profiles immune checkpoint blockade immune system function improved improved outcome in vivo inhibitor/antagonist knock-down men migration mutant neoplastic cell novel outcome forecast overexpression patient response pre-clinical pressure programmed cell death ligand 1 programmed cell death protein 1 receptor resistance mechanism response small hairpin RNA targeted treatment tool treatment strategy tumor tumor growth tumor progression tumor-immune system interactions

项目摘要

Project Summary Lung cancer is the leading cause of cancer-related deaths in the United States, and the 5-year survival rate of all lung cancer patients combined is only about 18%. The implementation of cancer immunotherapeutics for solid tumors such as lung cancers has shown great promise and provided the possibility for improved outcome in a small percentage of patients. However, the majority of patients show little to no response or acquire resistance during treatment with checkpoint inhibitors delivered as a monotherapy. Therefore, identifying resistance mechanisms and potential combination therapy approaches is a critical need to improve response rates to immune checkpoint inhibitors and patient prognosis. To address this, a clinically relevant in vivo shRNA dropout screen focused on genes encoding for FDA-approved drug targets (FDAome) was performed in epithelial and mesenchymal Kras/p53 (KP) mutant murine lung cancer cells. Mice were then treated with either isotype or anti- PD-1 antibody. Sequencing for the barcoded shRNAs revealed that Ntrk1 was significantly depleted from mesenchymal tumors challenged with PD-1 blockade compared to isotype treated tumors, suggesting it provides a survival advantage to these tumor cells when under immune system pressure. Preliminary data confirmed Ntrk1 transcript levels are upregulated in mesenchymal tumors treated with PD-1 inhibitors and cell lines derived from resistant tumors, and analysis of human NSCLC cell lines revealed that Ntrk1 mRNA levels correlate with a more aggressive, mesenchymal cell phenotype. Additionally, Ntrk1 overexpressing cells upregulate PD-L1 expression when co-cultured with splenocytes through upregulation of JAK signaling. Stable knockdown of Ntrk1 in mesenchymal murine KP mutant lung cancer cells reduced tumor growth in vivo and analysis of tumor- infiltrating T cell populations via flow cytometry showed that CD8+ T cell exhaustion was significantly reduced, whereas overexpression of Ntrk1 promoted CD8+ T cell exhaustion, thus decreasing effector status. These tumors also have an altered microenvironment, with upregulation of classically immunosuppressive cytokines such as IL-10. PD-1 protein levels were also significantly increased in Ntrk1-high human NSCLC cell lines, providing additional evidence that Ntrk1 may be a modulator of immune system functionality in human lung disease. The central hypothesis of the proposed work is that Ntrk1 upregulation causes acquired resistance to PD-1 blockade via aberrant JAK signaling and downstream CD8+ T cell dysfunction, thereby promoting tumor cell survival. A variety of powerful tools will be utilized to test this hypothesis, including time-lapse imaging of dynamic T cell-tumor cell interactions, genetically-engineered and syngeneic preclinical models of lung cancer to analyze immune subpopulations as a function of Ntrk1 expression, and IHC analyses of human NSCLC tissue samples. The goal of the proposed work is to provide strong evidence for a rational drug combination of Ntrk1 inhibitors with PD-1 blockade to be carried forward into the clinic to abrogate immune checkpoint blockade resistance and ultimately improve patient outcomes.

项目总结