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

• 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
• 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

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.

项目概要/摘要 纤维化是癌症的一个标志，它通过改变细胞结构来促进增殖、转移和免疫逃避。 肿瘤间质占肿瘤质量的90%。在纤维化中，致病性偏离体内平衡 导致肌成纤维细胞过度沉积细胞外基质（ECM），形成离散的区域 非解决性伤口修复。纤维化 ECM 的这些区域成为细胞表型的主要调节因子， 提供生物化学（即 ECM 成分和可溶性因子）和生物物理（即机械力） 和材料特性）促进肿瘤进展并限制免疫细胞浸润的线索。可溶性因子 这些纤维化器官的间隙内的物质流入周围淋巴结（LN）并诱发纤维化 淋巴结重塑，这是癌症和其他纤维化病理学预后不良的常见迹象。 LN 有一个 称为导管系统的独特微环境，它运输抗原并充当迁移 淋巴细胞的支架。在健康方面，其组织促进 T 细胞和抗原呈递之间的相互作用 细胞以确保针对癌症、病原体和损伤的强大免疫激活。成纤维细胞网状细胞 (FRC) 构建并包裹这个胶原蛋白网络并产生促进 T 细胞存活和 体内平衡。该 ECM 网络的破坏会导致 T 细胞失调和耗竭，从而影响淋巴结 疾病进展中的纤维化。淋巴结纤维化起始机制及淋巴结纤维化对 T 细胞的影响 人们对细胞功能知之甚少，但却代表了一个有吸引力的治疗机会。在其他组织中，纤维化 重塑机械地强化了微环境，启动整合素介导的信号级联。我 假设类似的机制通过 FRC 驱动 LN 纤维化，并试图探索 LN 的重塑如何 微环境影响纤维化和癌症中 T 细胞反应的发展。 该提案的第一个目标（F99 阶段）评估整合素信号传导是否通过促进 LN 纤维化 FRC 向肌成纤维细胞分化。这将通过分析特发性淋巴结来部分完成 肺纤维化和黑色素瘤患者具有先进的机械生物学（原子力显微镜）和 用于测量刚度、ECM 含量和 FRC/T 细胞表型的空间组学成像 (CODEX) 方法。这 然后将目标 1 中学到的知识和技能应用于目标 2（K00 阶段），以研究纤维化对 黑色素瘤小鼠模型中肿瘤引流淋巴结对抗肿瘤 T 细胞反应的影响。