Fibrotic remodeling of lymph nodes disrupts T cell function in fibrosis and cancer

淋巴结纤维化重塑破坏纤维化和癌症中的 T 细胞功能

基本信息

批准号：
10305424
负责人：
Grace C Bingham
金额：
$ 3.72万
依托单位：
UNIVERSITY OF VIRGINIA
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：
2021-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10305424
关键词：
Affect Animal Model Antigen-Presenting Cells Antigens Area Atomic Force Microscopy Biochemical Biology Biomedical Engineering Biophysics Cancer Biology Cancer Etiology Cancer Patient Cancer Research Project Cell Survival Cell physiology Cell surface Cells Cellular biology Cessation of life Chronic Cicatrix Clinical Collagen Combined Modality Therapy Complement Cues Deposition Development Disease Disease Progression Doctor of Philosophy Effectiveness Ensure Extracellular Matrix Extracellular Matrix Proteins Fibroblasts Fibronectins Fibrosis Functional disorder Future Genes Genetic Goals Health Homeostasis Human Image Immune Immune Evasion Immunology Immunotherapy In Vitro Infiltration Injury Integrin alphaVbeta3 Integrins Knowledge Link Lung Lymphocyte Malignant Neoplasms Malignant neoplasm of lung Measures Mechanics Mediating Mentors Methods Myofibroblast Neoplasm Metastasis Organ Outcome Pathogenicity Pathologic Pathology Pathway interactions Patients Pharmacology Phase Phenotype Process Production Prognosis Property Pulmonary Fibrosis Research Research Project Grants Reticular Cell Series Signal Transduction Site Stromal Cells Structure System T cell regulation T cell response T-Cell Activation T-Cell Development T-Lymphocyte Testing Therapeutic Tissues Training Transcription Coactivator Tumor-infiltrating immune cells Work adaptive immune response cancer immunotherapy cytokine draining lymph node idiopathic pulmonary fibrosis immune activation immunoengineering inhibitor/antagonist innovation interest interstitial lymph node microenvironment lymph nodes mechanical force mechanotransduction melanoma mouse model pathogen professor programs response scaffold senescence skills tumor tumor immunology tumor microenvironment tumor progression tumorigenesis wound healing

项目摘要

Project Summary/Abstract Fibrosis is a hallmark of cancer that promotes proliferation, metastasis, and immune evasion by altering the tumor stroma which accounts for up to 90% of tumor mass. In fibrosis, pathogenic departure from homeostasis results in the excessive deposition of extracellular matrix (ECM) by myofibroblasts, creating discrete regions of non-resolving wound repair. These regions of fibrotic ECM become dominant regulators of cell phenotype, providing both biochemical (i.e. ECM composition and soluble factors) and biophysical (i.e. mechanical forces and material properties) cues to promote tumor progression and restrict immune cell infiltration. Soluble factors within the interstitial space of these fibrotic organs drain into surrounding lymph nodes (LNs) and induce fibrotic remodeling in the LN, a common sign of poor prognosis in cancer and other fibrotic pathologies. LNs have a distinct microenvironment known as the conduit system, which traffics antigens and serves as a migratory scaffold for lymphocytes. In health, its organization facilitates interactions between T cells and antigen presenting cells to ensure robust immune activation in response to cancer, pathogens, and injury. Fibroblastic reticular cells (FRCs) construct and ensheath this collagenous network and produce cytokines that promote T cell survival and homeostasis. Disruption of this ECM network leads to T cell dysregulation and depletion, implicating lymph node fibrosis in disease progression. The mechanisms of fibrotic initiation in the LN and the effect of LN fibrosis in T cell function is poorly understood, yet represent an attractive therapeutic opportunity. In other tissues, fibrotic remodeling mechanically stiffens the microenvironment, initiating integrin-mediated signaling cascades. I hypothesize that similar mechanisms drive LN fibrosis by FRCs, and seek to explore how remodeling of the LN microenvironment affects development of T cell responses in fibrosis and cancer. The first aim of this proposal (F99 phase) evaluates whether integrin signaling drives LN fibrosis by promoting FRC-to-myofibroblast differentiation. This will be accomplished in part by analyzing LNs from Idiopathic Pulmonary Fibrosis and melanoma patients with advanced mechanobiological (atomic force microscopy) and spatial-omic imaging (CODEX) methods to measure stiffness, ECM content, and FRC/T cell phenotypes. The knowledge and skills learned in Aim 1 are then applied in Aim 2 (K00 phase) to study the impact of fibrosis in tumor draining LNs on anti-tumor T cell responses in murine models of melanoma.

项目摘要/摘要纤维化是癌症的标志，可通过改变来促进增殖，转移和免疫逃避肿瘤基质占肿瘤质量的90％。在纤维化中，致病性偏离稳态导致肌纤维细胞过度沉积细胞外基质（ECM），从而创建离散区域非分辨伤口修复。这些纤维化ECM的区域成为细胞表型的主要调节剂，提供生化（即ECM组成和可溶性因子）和生物物理（即机械力）材料特性）提示促进肿瘤进展并限制免疫细胞浸润。可溶性因素在这些纤维化器官的间质空间内，排入周围淋巴结（LN）并诱导纤维化在LN中进行重塑，这是癌症和其他纤维化病理预后不良的常见迹象。 lns有一个独特的微环境被称为导管系统，该系统运输抗原并用作迁移淋巴细胞的支架。在健康方面，其组织促进了T细胞与抗原呈现之间的相互作用细胞以确保响应癌症，病原体和损伤的强大免疫激活。成纤维细胞网细胞（FRC）构建和围绕该胶原网络的构建并产生促进T细胞存活和的细胞因子稳态。该ECM网络的破坏导致T细胞失调和耗竭，涉及淋巴结疾病进展中的纤维化。 LN中纤维化起始的机制以及LN纤维化在T中的作用细胞功能知之甚少，但代表了一个有吸引力的治疗机会。在其他组织中，纤维化重塑可以机械地将微环境僵硬，从而启动整联蛋白介导的信号级联。我假设类似的机制驱动FRC驱动LN纤维化，并寻求探索LN的重塑微环境影响纤维化和癌症中T细胞反应的发展。该提案的第一个目的（F99阶段）评估整联蛋白信号传导是否通过促进驱动LN纤维化驱动LN纤维化 frc-to-to Myofibroblast分化。这将部分通过分析特发性的LN来完成肺纤维化和黑色素瘤患者具有晚期机械生物学（原子力显微镜）和测量刚度，ECM含量和FRC/T细胞表型的空间 - 乐（Codex）方法。这然后将AIM 1中学到的知识和技能应用于AIM 2（K00阶段），以研究纤维化的影响黑色素瘤鼠模型中的抗肿瘤T细胞反应上的肿瘤在抗肿瘤T细胞反应上排出。