CSF1R+ Macrophages Sustain Pancreatic Tumor Growth through T Cell Suppression and Maintenance of Key Gene Programs that Define the Squamous Subtype.
View / Open Files
Authors
Candido, Juliana B
Morton, Jennifer P
Bailey, Peter
Campbell, Andrew D
Karim, Saadia A
Jamieson, Thomas
Lapienyte, Laura
Gopinathan, Aarthi
Clark, William
McGhee, Ewan J
Wang, Jun
Escorcio-Correia, Monica
Zollinger, Raphael
Roshani, Rozita
Drew, Lisa
Rishi, Loveena
Arkell, Rebecca
Evans, TR Jeffry
Nixon, Colin
Jodrell, Duncan I
Wilkinson, Robert W
Biankin, Andrew V
Barry, Simon T
Balkwill, Frances R
Sansom, Owen J
Publication Date
2018-05-01Journal Title
Cell Rep
ISSN
2211-1247
Publisher
Elsevier BV
Volume
23
Issue
5
Pages
1448-1460
Language
eng
Type
Article
Physical Medium
Print
Metadata
Show full item recordCitation
Candido, J. B., Morton, J. P., Bailey, P., Campbell, A. D., Karim, S. A., Jamieson, T., Lapienyte, L., et al. (2018). CSF1R+ Macrophages Sustain Pancreatic Tumor Growth through T Cell Suppression and Maintenance of Key Gene Programs that Define the Squamous Subtype.. Cell Rep, 23 (5), 1448-1460. https://doi.org/10.1016/j.celrep.2018.03.131
Abstract
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.
Keywords
T-Lymphocytes, Cell Line, Tumor, Macrophages, Animals, Humans, Mice, Carcinoma, Pancreatic Ductal, Pancreatic Neoplasms, Aniline Compounds, Heterocyclic Compounds, 2-Ring, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor, Neoplasm Proteins, Xenograft Model Antitumor Assays, Immunity, Cellular, Models, Immunological, Adult, Female, Male
Sponsorship
Cancer Research UK (15678)
Identifiers
External DOI: https://doi.org/10.1016/j.celrep.2018.03.131
This record's URL: https://www.repository.cam.ac.uk/handle/1810/284637
Statistics
Total file downloads (since January 2020). For more information on metrics see the
IRUS guide.