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

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 novel, coordinated, relationships between mesenchymal and immune cell subsets. Expression of CD105 demarks two stable and functionally distinct fibroblast lineages, that are ubiquitous in murine and human healthy tissues and tumors. Whereas CD105 positive 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, with a major contribution from type 1 conventional dendritic cells. Collectively, these results reveal two distinct fibroblast lineages conserved across tissues and species and highlight the importance of mesenchymal and immune cell interactions in restricting tumor growth.