Neutrophil Extracellular Traps and the Intersection of the Immune and Biophysical Microenvironments

中性粒细胞胞外陷阱以及免疫和生物物理微环境的交叉点

基本信息

批准号：
10668216
负责人：
Margo MacDonald
金额：
$ 4.77万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-11 至 2024-07-10
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10668216
关键词：
3-Dimensional 4T1 Affect Antitumor Response Automobile Driving Biophysics Breast Cancer Model CSF3 gene Cancer Model Cathepsin G Cause of Death Cell Mobility Cell physiology Cells Cessation of life Coculture Techniques Collaborations Collagen Crosslinker Cytotoxic T-Lymphocytes DNA Dendritic Cells Disease Disseminated Malignant Neoplasm Extracellular Matrix Histones IL8 gene Image Immune Immune response Immunofluorescence Immunologic Immunotherapy Lead Leukocyte Elastase Link Liquid substance Lung Lymphangiogenesis Lymphatic Macrophage Malignant Neoplasms Measures Mediating Modeling Mus Neoplasm Metastasis Neutrophil Activation Neutrophil Infiltration Patient-Focused Outcomes Patients Peptide Hydrolases Perfusion Physiological Play Porosity Prevention Process Proteins Research Resistance Role Site Solid Neoplasm Stains Structure T cell infiltration T cell therapy T-Cell Proliferation T-Lymphocyte Tissues Transgenic Model Vascular Endothelial Growth Factor D Work biophysical properties cancer cell cancer imaging cancer therapy cell motility cytokine cytotoxicity density experimental study extracellular implantation improved improved outcome in vitro Model in vivo lymph node microenvironment lymph nodes melanoma migration mouse model neutrophil novel novel therapeutic intervention overexpression pathogen physical property pressure prevent programs recruit response scaffold second harmonic generation imaging tumor tumor microenvironment tumor progression

项目摘要

Project Summary: While immunotherapy has revolutionized cancer treatment in recent years, major challenges still remain. Metastatic cancer remains difficult to treat, resulting in 90% of cancer deaths, and only 20-40% of patients respond to immunotherapy, with varying levels of response across cancers. In solid tumors, lymphatic activation, or lymphangiogenesis, is associated with both metastasis and improved response to immunotherapy, and more recently, neutrophil activation has also emerged as playing a key role in both of these processes. An important mechanism by which neutrophils promote cancer progression is through the formation of neutrophil extracellular traps (NETs). NETs are a mesh network of decondensed DNA dotted with histones and granular proteins, and they are released by neutrophils in order to trap and kill pathogens, or in response to tumor-secreted cytokines. Many of these proteins are proteases, which have the potential to remodel the extracellular matrix (ECM). In this proposal, we will explore the novel hypothesis that lymphatics and neutrophils collaborate in driving pro-metastatic programs in ways that alter the extracellular matrix (ECM) and host immune response. We will use immunofluorescence staining and second harmonic generation imaging of tumors, lungs, and lymph nodes from 4T1 and B16 murine models of cancer to characterize the cross-talk between NETosis, lymphangiogenesis and ECM in cancer metastasis. We will also use an inducible model of lymphangiogenesis that is specific to the lung in order to determine if the effect of NETosis on metastasis is specific to the pre-metastatic niche or the tumor microenvironment. We will use physiological artificial ECM and 3D perfusion models of the tumor-lymph node microenvironment with ex vivo tissues to determine how the biophysical properties of the tumor microenvironment affect NETosis and T cell cytotoxicity, and how NETosis affects tumor progression and response to immunotherapy. Results from this work could help us better predict which patients are likely to respond to immunotherapy and lead to new therapeutic strategies that make immunotherapy more effective in more patients. It will also increase our understanding of how the biophysical properties of the microenvironment affect immune cell function in general, which is likely an important factor in many disease processes.

项目摘要：虽然免疫疗法近年来彻底改变了癌症治疗，但主要挑战依然存在。转移性癌症仍然难以治疗，导致 90% 的癌症死亡，并且只有 20-40% 的患者对免疫疗法有反应，不同癌症的反应水平各不相同。在实体瘤、淋巴激活或淋巴管生成与转移和改善有关对免疫疗法的反应，最近，中性粒细胞激活也开始在免疫治疗的反应中发挥关键作用。这两个过程。中性粒细胞促进癌症进展的一个重要机制是通过中性粒细胞胞外陷阱（NET）的形成。 NET 是解压缩 DNA 的网状网络点缀着组蛋白和颗粒蛋白，它们由中性粒细胞释放以捕获和杀死病原体，或对肿瘤分泌的细胞因子的反应。这些蛋白质中有许多是蛋白酶，它们具有重塑细胞外基质（ECM）的潜力。在这个提案中，我们将探索小说假设淋巴管和中性粒细胞以改变转移的方式合作驱动促转移程序细胞外基质（ECM）和宿主免疫反应。我们将使用免疫荧光染色和第二步对 4T1 和 B16 小鼠癌症模型的肿瘤、肺和淋巴结进行谐波生成成像描述癌症转移中 NETosis、淋巴管生成和 ECM 之间的相互作用。我们还将使用肺部特异性的淋巴管生成诱导模型，以确定是否有影响转移上的 NETosis 特定于转移前的微环境或肿瘤微环境。我们将使用离体肿瘤淋巴结微环境的生理人工 ECM 和 3D 灌注模型组织以确定肿瘤微环境的生物物理特性如何影响 NETosis 和 T 细胞细胞毒性，以及 NETosis 如何影响肿瘤进展和对免疫治疗的反应。结果由此这项工作可以帮助我们更好地预测哪些患者可能对免疫疗法产生反应并带来新的结果使免疫疗法对更多患者更有效的治疗策略。也将增加我们的了解微环境的生物物理特性如何影响免疫细胞功能一般而言，这可能是许多疾病过程的重要因素。