Pro-tumor functions of neutrophils in squamous cell lung cancer

鳞状细胞肺癌中中性粒细胞的促肿瘤功能

基本信息

批准号：
10343793
负责人：
Trudy Gale Oliver
金额：
$ 6.66万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10343793
关键词：
3-Dimensional Ablation Adenocarcinoma Adenocarcinoma Cell Antibodies Architecture Biological Markers CTLA4 gene Cancer Biology Cancer Patient Cell Culture Techniques Cell physiology Cells Cessation of life Chemotaxis Clinical Trials Complex Coupled DNA Sequence Alteration Data Desmoplastic Development Diagnosis Disease Disease model Genetic Genetically Engineered Mouse Goals Histology Histopathology Human IL8RB gene Immune Immune Evasion Immune checkpoint inhibitor Immune response Immune system Immunocompetent Immunotherapy Innate Immune System Laboratories Light Lung Neoplasms Lymphocyte Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of lung Mediating Methods Mission Modeling Molecular Mus Mutant Strains Mice Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Organism Outcome Patient-Focused Outcomes Persons Pharmacology Play Production Prognosis Public Health Quality of life Reactive Oxygen Species Research Resistance Role Shapes Squamous Cell Squamous Cell Lung Carcinoma Squamous cell carcinoma Survival Rate Technology Testing Therapeutic Tumor stage United States United States National Institutes of Health Work angiogenesis anti-PD1 antibodies base cancer cell cancer diagnosis cancer therapy cell type chemotherapy clinically relevant combat effective therapy extracellular genetic approach human disease immune checkpoint blockade improved inhibitor innovation keratinization mouse model neoplastic cell neutrophil new therapeutic target novel novel therapeutic intervention patient subsets programmed cell death protein 1 response single-cell RNA sequencing small molecule tool transdifferentiation treatment response treatment strategy tumor tumor growth tumor initiation tumor microenvironment tumor progression tumor-immune system interactions

项目摘要

Project Summary Squamous cell lung cancer, a subtype of non-small cell lung cancer (NSCLC), is the second most common type of lung cancer. Also known as squamous cell carcinoma (SCC) of the lung, SCC is responsible for ~85,000 new cases of lung cancer each year and ~50,000 deaths in the United States alone. SCC is distinct from the other major subtype of NSCLC (adenocarcinoma) in terms of its histology, biomarker expression, genomic alterations, immune microenvironment and response to therapy. SCC has limited therapeutic options that are confined to chemotherapy and more recently, immunotherapy, which is only effective in a subset of patients. A major unmet need for the treatment of SCC is the identification of new therapeutic targets and treatment strategies to combat this disease. SCC has a unique histopathology and a complex microenvironment that is rich with desmoplastic stroma, keratinization and immune cells. Specifically, tumor-associated neutrophils (TANs) are enriched in mouse and human SCC, and neutrophil abundance correlates with poor prognosis and poor response to immunotherapy. Relatively little is known about how TANs impact SCC tumor progression and therapeutic response. It is notoriously difficult to model SCC in cell culture, which lacks the three-dimensional architecture of tumors, an intact immune system, and vasculature. Genetically-engineered mouse models (GEMMs) provide a complex living system that can highly recapitulate the human disease. Our laboratory pioneered the development of the first SOX2-driven SCC GEMM. We recently developed a rapid new GEMM based on alterations in Sox2/Lkb1/Nkx2-1 (SNL) where SCC tumors highly resemble the human disease in terms of histopathology, genetics, and immune microenvironment. This new SNL model represents a unique immune- competent tool to investigate how TANs shape tumor progression and therapeutic response. The objective of this study is to elucidate the role of TANs in squamous lung cancer development, progression and response to therapy. We hypothesize that TANs promote squamous cell fate by increasing reactive oxygen species (ROS), which are implicated in tumor transdifferentiation, and by promoting neutrophil extracellular traps (NETosis). To test these hypotheses, we will: 1) Determine the mechanism by which TANs alter tumor cell fate. 2) Determine whether TANs promote squamous lung cancer progression via ROS and/or NETosis. 3) Determine whether neutrophil depletion enhances response to chemotherapy and/or immunotherapy. This approach is innovative because we will employ: 1) our novel immune-competent SCC GEMM that recapitulates key features of the human disease, 2) neutrophil depletion strategies that are in clinical trials, and 3) state-of-the-art technologies including single cell RNA-sequencing and natural cancer-associated inhibitors of NETosis. This research is significant because TAN function in SCC is almost completely unexplored and TANs may represent a new therapeutic target for this intractable disease.

项目概要鳞状细胞肺癌是非小细胞肺癌 (NSCLC) 的一种亚型，是第二常见的类型肺癌。也称为肺鳞状细胞癌 (SCC)，SCC 导致约 85,000 例新发仅在美国，每年就有约 50,000 例肺癌病例和死亡病例。 SCC与其他的不同 NSCLC（腺癌）的主要亚型的组织学、生物标志物表达、基因组改变、免疫微环境和对治疗的反应。 SCC 的治疗选择有限，仅限于化疗和最近的免疫疗法仅对一小部分患者有效。一个重大的未满足 SCC治疗的需要是确定新的治疗靶点和治疗策略来对抗这种病。鳞状细胞癌具有独特的组织病理学和富含促纤维增生的复杂微环境基质、角化和免疫细胞。具体而言，肿瘤相关中性粒细胞 (TAN) 富含小鼠和人类 SCC 以及中性粒细胞丰度与不良预后和不良反应相关免疫疗法。关于 TAN 如何影响 SCC 肿瘤进展和治疗，人们知之甚少回复。众所周知，在细胞培养中模拟 SCC 非常困难，因为细胞培养缺乏三维架构肿瘤、完整的免疫系统和脉管系统。基因工程小鼠模型 (GEMM) 提供一个复杂的生命系统，可以高度概括人类疾病。我们的实验室开创了开发第一个 SOX2 驱动的 SCC GEMM。我们最近开发了一种基于快速新的 GEMM Sox2/Lkb1/Nkx2-1 (SNL) 的改变，其中 SCC 肿瘤在以下方面与人类疾病高度相似组织病理学、遗传学和免疫微环境。这个新的 SNL 模型代表了一种独特的免疫- 研究 TAN 如何影响肿瘤进展和治疗反应的有力工具。的目标本研究旨在阐明 TAN 在鳞状肺癌发生、进展和反应中的作用治疗。我们假设 TAN 通过增加活性氧 (ROS) 来促进鳞状细胞的命运，这与肿瘤转分化有关，并通过促进中性粒细胞胞外陷阱（NETosis）来实现。到检验这些假设，我们将： 1) 确定 TAN 改变肿瘤细胞命运的机制。 2）确定 TAN 是否通过 ROS 和/或 NETosis 促进鳞状肺癌进展。 3）判断是否中性粒细胞消耗增强对化疗和/或免疫疗法的反应。这个方法很有创新性因为我们将采用：1）我们新型的具有免疫能力的 SCC GEMM，它概括了 SCC 的关键特征人类疾病，2) 正在进行临床试验的中性粒细胞耗竭策略，以及 3) 最先进的技术包括单细胞 RNA 测序和天然癌症相关的 NETosis 抑制剂。这项研究是意义重大，因为 SCC 中的 TAN 功能几乎完全未被探索，而 TAN 可能代表一种新的这一疑难杂症的治疗目标。