CSF1R+ macrophages sustain pancreatic tumor growth through T cell suppression and maintenance of key gene programs that define the squamous subtype

Candido, J. B. 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 Reports, 23(5), pp. 1448-1460. (doi:10.1016/j.celrep.2018.03.131) (PMID:29719257)

Candido, J. B. 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 Reports, 23(5), pp. 1448-1460. (doi:10.1016/j.celrep.2018.03.131) (PMID:29719257)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Clark, Mr William and Bailey, Dr Peter and Morton, Dr Jennifer and Biankin, Professor Andrew and Jamieson, Mr Thomas and Nixon, Mr Colin and McGhee, Dr Ewan and Evans, Professor Thomas and Karim, Ms Saadia and Sansom, Professor Owen and Campbell, Dr Andrew
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., Arkhell, R., Evans, T.R. J., Nixon, C., Jordell, D. I., Wilkinson, R. W., Biankin, A. V., Barry, S. T., Balkwill, F. R., and Sansom, O. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Cell Reports
Publisher:Elsevier (Cell Press)
ISSN:2211-1247
ISSN (Online):2211-1247
Published Online:01 May 2018
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in Cell Reports 23(5):1448-1460
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
647981CR-UK Centre renewalKaren VousdenCancer Research UK (CRUK)18076RI CANCER SCIENCES