Single-cell analysis defines a pancreatic fibroblast lineage that supports anti-tumor immunity
Open accessAbstract
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.
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Depletion of FAP+ fibroblasts or targeting CXCL12 sensitizes PDAC to immune checkpoint blockade in preclinical models.
“Depletion of these fibroblasts, or targeting of CXCL12, sensitizes PDAC to immune checkpoint blockade in preclinical models151”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [151]
FAP-expressing CAFs also express high levels of CXCL12 and inhibit tumor T cell infiltration.
“CAFs expressing Fibroblast Activation Protein (FAP) also express high levels of CXCL12 and inhibit tumor T cell infiltration.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [151]
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References 98 · Cited by 337
- Authors
- Hutton, C., Heider, F., Blanco-Gomez, A., Banyard, A., Kononov, A., Zhang, X., Karim, S., Paulus-Hock, V., Watt, D., Steele, N., Kemp, S., Hogg, E. K. J., Kelly, J., Jackstadt, R.-F., Lopes, F., Menotti, M., Chisholm, L., Lamarca, A., Valle, J., Sansom, O. J., Springer, C., Malliri, A., Marais, R., Pasca di Magliano, M., Zelenay, S., Morton, J. P., & Jørgensen, C.
- Affiliations
- Cancer Research UK Manchester Institute (GB)
- Cancer Research UK Scotland Institute (GB)
- University of Michigan (US)
- University of Manchester (GB)
- Corresponding author
- Jørgensen, Claus
- ORCID
- Blanco-Gomez, Adrian
- Banyard, Antonia
- Kononov, Alexander
- Zhang, Xiaohong
- Karim, Saadia
- Paulus-Hock, Viola
- Watt, Dale
- Steele, Nina
- Kemp, Samantha
- Hogg, Elizabeth K.J.
- Kelly, Joanna
- Menotti, Matteo
- Valle, Juan
- Sansom, Owen J.
- Springer, Caroline
- Malliri, Angeliki
- Marais, Richard
- Zelenay, Santiago
- Morton, Jennifer P.
- Jørgensen, Claus
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2021-09
- Volume
- 39
- Issue
- 9
- Pages
- 1227-1244.e20
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC8443274
- OpenAlex
- W3173255621
- Cited by
- 337
- References
- 98
- Citations by year
- 2026: 58 · 2025: 56 · 2024: 79 · 2023: 63 · 2022: 67 · 2021: 13 · 2020: 1
- FWCI
- 20.37
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion, cc-by-nc-nd)
- Discovery Research Portal (University of Dundee) (submittedVersion, cc-by-nc-nd)
- Funders
- Novartis
- ERC (ERC-2017-COG 772577)
- Cancer Research Institute
- Cancer Research UK (A17196, A21139, A25236, A29996, C5759/A27412)
- Conquer Cancer Foundation
- Institute of Cancer Research
- European Research Council
- AstraZeneca
- Pfizer
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- pancreatic fibroblasts, pancreatic ductal adenocarcinoma, fibroblast heterogeneity, CD105, tumor stroma, antitumor immunity, adaptive immunity, tumor microenvironment
- MeSH terms
- Cell Plasticity, Endoglin, Cancer-Associated Fibroblasts, Animals, Humans, Neoplasm Transplantation, Pancreatic Neoplasms, Gene Expression Regulation, Neoplastic, Case-Control Studies, Gene Expression Profiling, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Mice, Adaptive Immunity, Single-Cell Analysis, Tumor Microenvironment
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