Cross-Species Single-Cell Analysis of Pancreatic Ductal Adenocarcinoma Reveals Antigen-Presenting Cancer-Associated Fibroblasts
Cross-Species Single-Cell Analysis of Pancreatic Ductal Adenocarcinoma Reveals Antigen-Presenting Cancer-Associated Fibroblasts
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DOI：
10.1158/2159-8290.cd-19-0094
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发表时间：
2019-08-01
期刊：
影响因子：
28.2
通讯作者：
Tuveson, David A.
中科院分区：
文献类型：
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作者：
Elyada, Ela;Bolisetty, Mohan;Tuveson, David A.
癌相关成纤维细胞（CAF）在胰腺导管腺癌（PDAC）的进展和耐药过程中起着重要作用。尽管CAF异质性的程度仍未明确，但CAF构成了由几种最近描述的亚型组成的多样化细胞群。在这里，我们使用单细胞RNA测序来彻底表征人类和小鼠PDAC肿瘤的肿瘤和肿瘤微环境含量。我们证实了肌成纤维细胞CAFs和炎性CAFs的存在，并在体内定义了它们独特的基因特征。此外，我们描述了一种新的表达MHC II类和CD74的caf群体，但不表达经典的共刺激分子。我们将这种细胞群称为“抗原呈递CAFs”，并发现它们在模型系统中以抗原特异性的方式激活CD4(+) T细胞，证实了它们假定的免疫调节能力。我们的跨物种分析为研究CAF亚型在PDAC免疫和进展中的不同功能铺平了道路。意义：了解胰腺导管腺癌中成纤维细胞的全谱异质性对于开发特异性靶向促肿瘤CAFs的治疗方法至关重要。这项工作鉴定了表达MHC ii类的caf，它们具有向CD4(+) T细胞呈递抗原的能力，并可能调节胰腺肿瘤的免疫反应。
Cancer-associated fibroblasts (CAF) are major players in the progression and drug resistance of pancreatic ductal adenocarcinoma (PDAC). CAFs constitute a diverse cell population consisting of several recently described subtypes, although the extent of CAF heterogeneity has remained undefined. Here we use single-cell RNA sequencing to thoroughly characterize the neoplastic and tumor microenvironment content of human and mouse PDAC tumors. We corroborate the presence of myofibroblastic CAFs and inflammatory CAFs and define their unique gene signatures in vivo. Moreover, we describe a new population of CAFs that express MHC class II and CD74, but do not express classic costimulatory molecules. We term this cell population "antigen-presenting CAFs" and find that they activate CD4(+) T cells in an antigen-specific fashion in a model system, confirming their putative immune-modulatory capacity. Our cross-species analysis paves the way for investigating distinct functions of CAF subtypes in PDAC immunity and progression.SIGNIFICANCE: Appreciating the full spectrum of fibroblast heterogeneity in pancreatic ductal adenocarcinoma is crucial to developing therapies that specifically target tumor-promoting CAFs. This work identifies MHC class II-expressing CAFs with a capacity to present antigens to CD4(+) T cells, and potentially to modulate the immune response in pancreatic tumors.