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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：
Huocong Huang
金额：
$ 24.9万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
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

来源：
https://reporter.nih.gov/project-details/10732793
关键词：
Address Adhesions Antibody-drug conjugates Antigen Presentation CD4 Positive T Lymphocytes Cells Clinical Cues Data Disease Drug Delivery Systems Embryo Epithelial Cells Exclusion Extracellular Matrix Fibroblasts Fibrosis Genes Immune Evasion Immunosuppression Immunotherapy Impairment In Vitro Inflammatory Interleukin-1 Invaded Malignant Neoplasms Membrane Mesenchymal Mesoderm Mesothelial Cell Mesothelium Monoclonal Antibodies Myocardial Infarction Operative Surgical Procedures Organ Outcome Pancreatic Ductal Adenocarcinoma Pathologic Peripheral Peritoneal Phase Phenotype Physiological Population Preclinical Testing Process Reporting Resistance Signal Pathway Solid Neoplasm Source Surface Survival Rate System T cell infiltration T cell regulation T-Cell Activation T-Lymphocyte Testing Tissues Training Transforming Growth Factor beta Tumor Volume Vaccines anti-cancer cancer cell chemotherapy chimeric antigen receptor T cells combat immune checkpoint blockade immune resistance in vivo Model lipid biosynthesis mesothelin mouse genetics neglect novel novel strategies prevent single-cell RNA sequencing targeted cancer therapy tumor tumor microenvironment tumor progression tumor-immune system interactions wound healing

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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