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:
  • 金额:
    $ 3.79万
  • 依托单位:
  • 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

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

项目成果

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Grace C Bingham其他文献

Grace C Bingham的其他文献

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{{ truncateString('Grace C Bingham', 18)}}的其他基金

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:
    10305424
  • 财政年份:
    2021
  • 资助金额:
    $ 3.79万
  • 项目类别:

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