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dc.contributor.authorCandido, Juliana B
dc.contributor.authorMorton, Jennifer P
dc.contributor.authorBailey, Peter
dc.contributor.authorCampbell, Andrew D
dc.contributor.authorKarim, Saadia A
dc.contributor.authorJamieson, Thomas
dc.contributor.authorLapienyte, Laura
dc.contributor.authorGopinathan, Aarthi
dc.contributor.authorClark, William
dc.contributor.authorMcGhee, Ewan J
dc.contributor.authorWang, Jun
dc.contributor.authorEscorcio-Correia, Monica
dc.contributor.authorZollinger, Raphael
dc.contributor.authorRoshani, Rozita
dc.contributor.authorDrew, Lisa
dc.contributor.authorRishi, Loveena
dc.contributor.authorArkell, Rebecca
dc.contributor.authorEvans, TR Jeffry
dc.contributor.authorNixon, Colin
dc.contributor.authorJodrell, Duncan
dc.contributor.authorWilkinson, Robert W
dc.contributor.authorBiankin, Andrew V
dc.contributor.authorBarry, Simon T
dc.contributor.authorBalkwill, Frances R
dc.contributor.authorSansom, Owen J
dc.date.accessioned2018-11-06T00:30:13Z
dc.date.available2018-11-06T00:30:13Z
dc.date.issued2018-05-01
dc.identifier.issn2211-1247
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/284637
dc.description.abstractPancreatic 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.
dc.format.mediumPrint
dc.languageeng
dc.publisherElsevier BV
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectT-Lymphocytes
dc.subjectCell Line, Tumor
dc.subjectMacrophages
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectCarcinoma, Pancreatic Ductal
dc.subjectPancreatic Neoplasms
dc.subjectAniline Compounds
dc.subjectHeterocyclic Compounds, 2-Ring
dc.subjectReceptors, Granulocyte-Macrophage Colony-Stimulating Factor
dc.subjectNeoplasm Proteins
dc.subjectXenograft Model Antitumor Assays
dc.subjectImmunity, Cellular
dc.subjectModels, Immunological
dc.subjectAdult
dc.subjectFemale
dc.subjectMale
dc.titleCSF1R+ Macrophages Sustain Pancreatic Tumor Growth through T Cell Suppression and Maintenance of Key Gene Programs that Define the Squamous Subtype.
dc.typeArticle
prism.endingPage1460
prism.issueIdentifier5
prism.publicationDate2018
prism.publicationNameCell Rep
prism.startingPage1448
prism.volume23
dc.identifier.doi10.17863/CAM.32011
dcterms.dateAccepted2018-03-28
rioxxterms.versionofrecord10.1016/j.celrep.2018.03.131
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-05
dc.contributor.orcidJodrell, Duncan [0000-0001-9360-1670]
dc.identifier.eissn2211-1247
rioxxterms.typeJournal Article/Review
pubs.funder-project-idCancer Research UK (15678)


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International