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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：
10470223
负责人：
Grace C Bingham
金额：
$ 3.79万
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/10470223
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 Lymphocyte Malignant Neoplasms Malignant neoplasm of lung Measures Mechanics Mediating Mentors Methods Mus 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 innovation interest interstitial lymph node microenvironment lymph nodes mechanical force mechanical signal 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.

项目总结/文摘