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CSF1R(+) macrophages sustain pancreatic tumor growth through T cell suppression and maintenance of key gene programs that define the squamous subtype
Open accessAbstract
Pancreatic ductal adenocarcinoma (PDAC) is resistant to most therapies including single-agent immunotherapy and has a dense desmoplastic stroma, and most patients present with advanced metastatic disease. We reveal that macrophages are the dominant leukocyte population both in human PDAC stroma and autochthonous models, with an important functional contribution to the squamous subtype of human PDAC. We targeted macrophages in a genetic PDAC model using AZD7507, a potent selective inhibitor of CSF1R. AZD7507 caused shrinkage of established tumors and increased mouse survival in this difficult-to-treat model. Malignant cell proliferation diminished, with increased cell death and an enhanced T cell immune response. Loss of macrophages rewired other features of the TME, with global changes in gene expression akin to switching PDAC subtypes. These changes were markedly different to those elicited when neutrophils were targeted via CXCR2. These results suggest targeting the myeloid cell axis may be particularly efficacious in PDAC, especially with CSF1R inhibitors.
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“targeting MDSCs and/or TAMs improves adaptive immune responses in mouse models of pancreatic cancer and can potentiate checkpoint inhibition approaches176,177,179,180”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [179]
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Metadata
- Authors
- Candido, J. B., Morton, J. P., Bailey, P., Campbell, A. D., Karim, S. A., Jamieson, T., Lapienyte, L., Gopinathan, A., Clark, W., McGhee, E. J., Wang, J., Escorcio-Correia, M., Zollinger, R., Roshani, R., Drew, L., Rishi, L., Arkell, R., Evans, T. R. J., Nixon, C., Jodrell, D. I., Wilkinson, R. W., Biankin, A. V., Barry, S. T., Balkwill, F. R., & Sansom, O. J.
- Affiliations
- Queen Mary University of London (GB)
- Cancer Research UK Scotland Institute (GB)
- University of Glasgow (GB)
- University of Cambridge (GB)
- AstraZeneca (United States) (US)
- AstraZeneca (United Kingdom) (GB)
- Corresponding author
- Sansom, Owen J.
- ORCID
- Candido, Juliana B.
- Morton, Jennifer P.
- Bailey, Peter
- Campbell, Andrew D.
- Karim, Saadia A.
- Jamieson, Thomas
- Gopinathan, Aarthi
- Clark, William
- McGhee, Ewan J.
- Wang, Jun
- Drew, Lisa
- Evans, T.R. Jeffry
- Nixon, Colin
- Jodrell, Duncan I.
- Wilkinson, Robert W.
- Biankin, Andrew V.
- Barry, Simon T.
- Balkwill, Frances R.
- Sansom, Owen J.
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2018-05
- Volume
- 23
- Issue
- 5
- Pages
- 1448-1460
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC5946718
- OpenAlex
- W2799476413
- Cited by
- 224
- References
- 45
- Citations by year
- 2026: 20 · 2025: 14 · 2024: 24 · 2023: 29 · 2022: 28 · 2021: 42 · 2020: 40 · 2019: 23 · 2018: 4
- FWCI
- 11.71
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Queen Mary Research Online (Queen Mary University of London) (submittedVersion, cc-by)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- Cancer Research UK
- University of Cambridge
- AstraZeneca
- Atlantic Philanthropies (A20409, A16354, C596/A17196, A25142, A25265, C596/A18076)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- pancreatic ductal adenocarcinoma, CSF1R, tumor-associated macrophages, T cell suppression, tumor microenvironment, desmoplasia, CXCR2, neutrophils, tumor growth, gene expression reprogramming
- MeSH terms
- Adult, Aniline Compounds, Animals, Female, Heterocyclic Compounds, 2-Ring, Humans, Immunity, Cellular, Macrophages, Male, Neoplasm Proteins, Pancreatic Neoplasms, T-Lymphocytes, Receptor, Macrophage Colony-Stimulating Factor, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor, Models, Immunological, Carcinoma, Pancreatic Ductal, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice
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