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Mesothelial cell-derived antigen-presenting cancer-associated fibroblasts induce expansion of regulatory T cells in pancreatic cancer
Cancer Cell ( IF 48.8 ) Pub Date : 2022-05-05 , DOI: 10.1016/j.ccell.2022.04.011
Huocong Huang 1 , Zhaoning Wang 2 , Yuqing Zhang 3 , Rachana N Pradhan 4 , Debolina Ganguly 3 , Raghav Chandra 1 , Gilbert Murimwa 1 , Steven Wright 5 , Xiaowu Gu 6 , Ravikanth Maddipati 7 , Sören Müller 4 , Shannon J Turley 4 , Rolf A Brekken 8
Affiliation  

Recent studies have identified a unique cancer-associated fibroblast (CAF) population termed antigen-presenting CAFs (apCAFs), characterized by the expression of major histocompatibility complex class II molecules, suggesting a function in regulating tumor immunity. Here, by integrating multiple single-cell RNA-sequencing studies and performing robust lineage-tracing assays, we find that apCAFs are derived from mesothelial cells. During pancreatic cancer progression, mesothelial cells form apCAFs by downregulating mesothelial features and gaining fibroblastic features, a process induced by interleukin-1 and transforming growth factor β. apCAFs directly ligate and induce naive CD4+ T cells into regulatory T cells (Tregs) in an antigen-specific manner. Moreover, treatment with an antibody targeting the mesothelial cell marker mesothelin can effectively inhibit mesothelial cell to apCAF transition and Treg formation induced by apCAFs. Taken together, our study elucidates how mesothelial cells may contribute to immune evasion in pancreatic cancer and provides insight on strategies to enhance cancer immune therapy.



中文翻译:


间皮细胞衍生的抗原呈递癌症相关成纤维细胞诱导胰腺癌中调节性 T 细胞的扩增



最近的研究发现了一种独特的癌症相关成纤维细胞 (CAF) 群体,称为抗原呈递 CAF (apCAF),其特征是表达主要组织相容性复合物 II 类分子,表明具有调节肿瘤免疫的功能。在这里,通过整合多个单细胞 RNA 测序研究并进行强大的谱系追踪分析,我们发现 apCAF 源自间皮细胞。在胰腺癌进展过程中,间皮细胞通过下调间皮特征并获得成纤维细胞特征来形成 apCAF,这是由白细胞介素 1 和转化生长因子 β 诱导的过程。 apCAF 以抗原特异性方式直接连接并诱导初始 CD4 + T 细胞转化为调节性 T 细胞 (Treg)。此外,用靶向间皮细胞标志物间皮素的抗体治疗可以有效抑制间皮细胞向apCAF的转变以及apCAF诱导的Treg形成。总而言之,我们的研究阐明了间皮细胞如何促进胰腺癌的免疫逃避,并提供了增强癌症免疫治疗策略的见解。

更新日期:2022-05-05
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