Function of mesothelial cells in the tumor microenvironment of pancreatic ductal adenocarcinoma

间皮细胞在胰腺导管腺癌肿瘤微环境中的功能

基本信息

  • 批准号:
    10732793
  • 负责人:
  • 金额:
    $ 24.9万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-12-01 至 2025-11-30
  • 项目状态:
    未结题

项目摘要

Project Summary/Abstract Pancreatic ductal adenocarcinoma (PDA) is a lethal disease characterized by extensive desmoplasia caused by the rapid expansion of cancer-associated fibroblasts (CAFs), resulting in the formation of dense stroma. CAFs stimulate cancer progression by secreting a variety of factors that support cancer cells and facilitate immunosuppression. In addition, they also secrete extracellular matrix (ECM) that provides survival and invasion cues to cancer cells and impairs drug delivery. Recently, several populations of CAFs with distinct functions have been characterized in PDA by our group and others using single cell RNA sequencing (scRNA seq). One population is characterized as myofibroblastic CAFs (myCAFs), another population is characterized as inflammatory CAFs (iCAFs), the third population was first identified as antigen-presenting CAFs (apCAFs), which express MHC II molecules and can effectively present antigen to T cells. My preliminary data demonstrated that apCAFs are mesothelial cells. Mesothelial cells form a continuous layer of epithelial cells known as mesothelium. The mesothelium is traditionally thought to be a membrane providing a non-adhesive surface covering organs and tissues. However, until the description of apCAF population, mesothelial cells have been neglected as a potential functional constituent of the tumor microenvironment. My preliminary data suggest that during PDA progression, mesothelial cells go through a mesothelial-fibroblastic transition (MFT), in which they down-regulate MHC II molecules that are required for CD4+ T cells activation, and up-regulate fibroblast genes that have been known to prevent T cell infiltration and activation. Peripheral T cell exclusion is a major immune evasion phenotype in PDA, and my preliminary data show that this exclusion occurs at the region where mesothelial cells are transitioning to CAFs. Therefore, MFT might be an important mechanism of immune evasion and understanding this process is critical. In this proposal, I will test the hypothesis that the fibroblastic transition of mesothelial cells promotes immune evasion in PDA and identify potential strategies to inhibit this process. I propose the following two aims: Aim 1. Determine the fate of mesothelial cells during PDA progression. Aim 2. Determine the functions of MFT on immune evasion. The outcome of the proposed study has the potential to shift the paradigm of tumor microenvironment studies, identify novel strategies to target CAFs and overcome resistance of immune therapies in PDA and other tumor types.
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项目成果

期刊论文数量(0)
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会议论文数量(0)
专利数量(0)

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Huocong Huang其他文献

Huocong Huang的其他文献

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{{ truncateString('Huocong Huang', 18)}}的其他基金

Function of mesothelial cells in the tumor microenvironment of pancreatic ductal adenocarcinoma
间皮细胞在胰腺导管腺癌肿瘤微环境中的功能
  • 批准号:
    10215170
  • 财政年份:
    2021
  • 资助金额:
    $ 24.9万
  • 项目类别:
Function of mesothelial cells in the tumor microenvironment of pancreatic ductal adenocarcinoma
间皮细胞在胰腺导管腺癌肿瘤微环境中的功能
  • 批准号:
    10372149
  • 财政年份:
    2021
  • 资助金额:
    $ 24.9万
  • 项目类别:

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