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

项目摘要/摘要 摘要胰腺导管腺癌(Pda)是一种以广泛的促结缔组织增生为特征的致命性疾病。 通过癌症相关成纤维细胞(CAF)的快速扩张，导致致密间质的形成。 CAF通过分泌多种支持癌细胞和促进肿瘤进展的因子来刺激癌症的进展 免疫抑制。此外，它们还分泌细胞外基质(ECM)，提供生存和 侵袭提示癌细胞，并损害药物的输送。最近，几个群体的CAF具有明显的 我们的团队和其他人使用单细胞RNA测序(ScRNA)对PDA的功能进行了表征 SEQ)。一个群体被描述为肌成纤维细胞CAF(MyCAF)，另一个群体被描述为MyCAF 作为炎症性CAF(ICAF)，第三个群体首先被鉴定为抗原提呈CAF(ApCAF)， 它们表达MHC II分子，并能有效地将抗原递呈给T细胞。我的初步数据 证实apCAF为间皮细胞。间皮细胞形成一层连续的上皮细胞 被称为间皮细胞。传统上，间皮细胞被认为是一种提供非粘附性的膜 覆盖器官和组织的表面。然而，直到apCAF群体的描述，间皮细胞 作为肿瘤微环境的一个潜在功能成分而被忽视。我的初步数据 提示在PDA进展过程中，间皮细胞经历了间皮-成纤维细胞转化(MFT)， 其中，它们下调CD4+T细胞激活所需的MHC II分子，并上调 已知可防止T细胞渗透和激活的成纤维细胞基因。外周T细胞排斥是 PDA的一种主要免疫逃避表型，我的初步数据显示，这种排除发生在 间皮细胞向CAF过渡的区域。因此，MFT可能是一种重要的机制。 免疫规避和理解这一过程至关重要。在这个提议中，我将测试假设 间皮细胞的成纤维细胞转化促进PDA的免疫逃避和识别潜力 抑制这一过程的策略。我提出了以下两个目标：目标1.决定间皮细胞的命运 在PDA进展过程中的细胞。目的2.确定MFT在免疫逃避中的作用。结果是 这项拟议的研究有可能改变肿瘤微环境研究的范式，确定新的 靶向CAF的策略和克服PDA和其他肿瘤类型免疫治疗的耐药性。

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.