Format

Send to

Choose Destination
Cell Rep. 2018 May 1;23(5):1448-1460. doi: 10.1016/j.celrep.2018.03.131.

CSF1R+ Macrophages Sustain Pancreatic Tumor Growth through T Cell Suppression and Maintenance of Key Gene Programs that Define the Squamous Subtype.

Author information

1
Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.
2
Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK.
3
Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK.
4
Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK.
5
Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.
6
Bioscience, Oncology, iMED Biotech Unit, AstraZeneca, Boston, MA, USA.
7
MedImmune Ltd, Granta Park, Cambridge CB21 6GH, UK.
8
Bioscience, Oncology, iMED Biotech Unit, AstraZeneca, Cambridge, UK.
9
Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK. Electronic address: o.sansom@beatson.gla.ac.uk.

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:

CSF1R; T cells; macrophages; pancreatic cancer

PMID:
29719257
PMCID:
PMC5946718
DOI:
10.1016/j.celrep.2018.03.131
[Indexed for MEDLINE]
Free PMC Article

Publication type, MeSH terms, Substances, Grant support

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center