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: 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
• 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

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.

项目概要/摘要 胰腺导管腺癌（PDA）是一种致命性疾病，其特征是引起广泛的结缔组织增生 通过癌症相关成纤维细胞（CAF）的快速扩张，导致致密基质的形成。 CAF 通过分泌多种支持癌细胞并促进癌症进展的因子来刺激癌症进展。 免疫抑制。此外，它们还分泌细胞外基质（ECM），提供生存和 癌细胞的入侵信号并损害药物输送。最近，几个具有不同特征的 CAF 群体 我们小组和其他人使用单细胞 RNA 测序（scRNA）在 PDA 中表征了功能 序列）。一个群体的特征为肌成纤维细胞 CAF (myCAF)，另一群体的特征为 作为炎症性CAF（iCAF），第三个群体首先被鉴定为抗原呈递CAF（apCAF）， 表达MHC II分子并能有效地将抗原呈递给T细胞。我的初步数据 证明 apCAF 是间皮细胞。间皮细胞形成连续的上皮细胞层 称为间皮。传统上认为间皮是一种提供非粘附性的膜 表面覆盖器官和组织。然而，直到 apCAF 群体的描述，间皮细胞 作为肿瘤微环境的潜在功能成分而被忽视。我的初步数据 表明在 PDA 进展过程中，间皮细胞经历间皮-成纤维细胞转变 (MFT)， 其中它们下调 CD4+ T 细胞激活所需的 MHC II 分子，并上调 已知可阻止 T 细胞浸润和激活的成纤维细胞基因。外周T细胞排除是 PDA 中的一个主要免疫逃避表型，我的初步数据表明，这种排除发生在 间皮细胞转变为 CAF 的区域。因此，MFT可能是一个重要的机制。 免疫逃避和理解这个过程至关重要。在这个提案中，我将测试以下假设： 间皮细胞的成纤维细胞转化促进 PDA 中的免疫逃避并识别潜在的 抑制这一过程的策略。我提出以下两个目标： 目标 1. 确定间皮细胞的命运 PDA 进展期间的细胞。目的2.确定MFT在免疫逃避中的作用。结果 拟议的研究有可能改变肿瘤微环境研究的范式，确定新的 针对 CAF 并克服 PDA 和其他肿瘤类型免疫疗法耐药性的策略。