Mesothelial cell-derived antigen-presenting cancer-associated fibroblasts induce expansion of regulatory T cells in pancreatic cancer

作者：Huocong Huang, Zhaoning Wang, Yuqing Zhang, Rachana Pradhan, Debolina Ganguly, Raghav Chandra, Gilbert Z. Murimwa, Steven H. Wright, Xiaowu Gu, Ravikanth Maddipati, Sören Müller, Shannon J. Turley, Rolf A. Brekken · 发表于：Cancer Cell · 年份：2022 · DOI：10.1016/j.ccell.2022.04.011 · 被引用次数：541 · 研究领域：Pancreatic and Hepatic Oncology Research、Immune cells in cancer、Single-cell and spatial transcriptomics

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.