Single-cell analysis defines a pancreatic fibroblast lineage that supports anti-tumor immunity

Colin Hutton, Felix Heider, Adrian Blanco-Gomez, Antonia Banyard, Alexander Kononov, Xiaohong Zhang, Saadia Karim, Viola Paulus-Hock, Dale Watt, Nina Steele, Samantha Kemp, Elizabeth K. J. Hogg, Joanna Kelly, Rene Filip Jackstadt, Filipa Lopes, Matteo Menotti, Luke Chisholm, Angela Lamarca, Juan Valle, Owen J. SansomCaroline Springer, Angeliki Malliri, Richard Marais, Marina Pasca di Magliano, Santiago Zelenay, Jennifer P. Morton, Claus Jørgensen (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

59 Citations (Scopus)
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Abstract

Fibroblasts display extensive transcriptional heterogeneity, yet functional annotation and characterization of their heterocellular relationships remains incomplete. Using mass cytometry, we chart the stromal composition of 18 murine tissues and 5 spontaneous tumor models, with an emphasis on mesenchymal phenotypes. This analysis reveals extensive stromal heterogeneity across tissues and tumors, and identifies coordinated relationships between mesenchymal and immune cell subsets in pancreatic ductal adenocarcinoma. Expression of CD105 demarks two stable and functionally distinct pancreatic fibroblast lineages, which are also identified in murine and human healthy tissues and tumors. Whereas CD105-positive pancreatic fibroblasts are permissive for tumor growth in vivo, CD105-negative fibroblasts are highly tumor suppressive. This restrictive effect is entirely dependent on functional adaptive immunity. Collectively, these results reveal two functionally distinct pancreatic fibroblast lineages and highlight the importance of mesenchymal and immune cell interactions in restricting tumor growth.

Original languageEnglish
Pages (from-to)1227-1244.e20
Number of pages39
JournalCancer Cell
Volume39
Issue number9
Early online date22 Jul 2021
DOIs
Publication statusPublished - 13 Sep 2021

Keywords

  • CAF
  • cancer-associated fibroblast lineages
  • CD105
  • CyTOF
  • Eng
  • mass cytometry
  • pancreatic cancer
  • tumor microenvironment
  • tumor-restrictive fibroblasts

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