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dc.contributor.authorO'Malley, Grace
dc.contributor.authorTreacy, Oliver
dc.contributor.authorLynch, Kevin
dc.contributor.authorNaicker, Serika D.
dc.contributor.authorLeonard, Niamh A.
dc.contributor.authorLohan, Paul
dc.contributor.authorDunne, Philip D.
dc.contributor.authorRitter, Thomas
dc.contributor.authorEgan, Laurence J.
dc.contributor.authorRyan, Aideen E.
dc.date.accessioned2019-08-27T12:13:11Z
dc.date.issued2018-11
dc.identifier.citationO'Malley, Grace, Treacy, Oliver, Lynch, Kevin, Naicker, Serika D., Leonard, Niamh A., Lohan, Paul, Dunne, Philip D., Ritter, Thomas, Egan, Laurence J., Ryan, Aideen E. (2018). Stromal Cell PD-L1 Inhibits CD8+ T-cell Antitumor Immune Responses and Promotes Colon Cancer. Cancer Immunology Research, 6(11), 1426-1441. doi: 10.1158/2326-6066.cir-17-0443en_IE
dc.identifier.issn2326-6074
dc.identifier.urihttp://hdl.handle.net/10379/15350
dc.description.abstractStromal cells of mesenchymal origin reside below the epithelial compartment and provide structural support in the intestine. These intestinal stromal cells interact with both the epithelial cell compartments, as well as infiltrating hematopoietic immune cells. The importance of these cells in regulating immune homeostasis during inflammation is well recognized. However, little is known about their function and phenotype in the inflammatory tumor microenvironment. Using a syngeneic, immunogenic model of colorectal cancer, we showed that TNFa-initiated inflammatory signaling in CT26 colorectal cancer cells selectively induced PD-L1 expression in stromal cells. Using CD274 shRNA and antibodymediated approaches, we showed that stromal cell PD-L1 potentiated enhanced immunosuppression, characterized by inhibition of activated CD8(+) granzyme B-secreting T cells in vitro, and the inhibition of CD8(+) effector cells was associated with enhanced tumor progression. Stromal cell immunosuppressive and tumor-promoting effects could be reversed with administration of anti-PD-1 in vivo. We validated our findings of stromal cell CD274 expression in two cohorts of clinical samples and also observed PD-L1 induction on human stromal cells in response to exposure to the inflammatory secretome fromhuman colon cancer cells, irrespective of microsatellite instability. Collectively, our data showed that tumor-associated stromal cells support T-cell suppression by PD-L1 induction, which is dependent on colon cancer inflammatory signaling. Our findings reveal a key role of mesenchymal stromal cells PD-L1 in suppression of CD8(+) antitumor immune responses and potentiation of colorectal cancer progression. (C) 2018 AACR.en_IE
dc.description.sponsorshipThe authors would like to acknowledge financial support from the Irish Cancer Society (CRF12RYA) and Science Foundation Ireland (15/SIRG/3456) and Galway University Foundation to Dr. A.E. Ryan, a postgraduate scholarship from the Irish Research Council (GOIPG/2013/998) to G O’Malley, and a grant from Science Foundation Ireland (12/IA/1624) to T. Ritter. The authors thank Professor Matthew Griffin, Professor Rhodri Ceredig, and Dr. Declan McKernan for helpful discussions; Ms. Georgina Shaw, Dr. Joana Cabral, and Ms. Athina Rigalou for technical assistance; and Dr. Shirley Hanley in the NUIG Flow Cytometry core facility for technical expertise. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.en_IE
dc.formatapplication/pdfen_IE
dc.language.isoenen_IE
dc.publisherAmerican Association for Cancer Researchen_IE
dc.relation.ispartofCancer Immunology Researchen
dc.rightsAttribution-NonCommercial-NoDerivs 3.0 Ireland
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/3.0/ie/
dc.subjectGENE-EXPRESSION DEFINESen_IE
dc.subjectNF-KAPPA-Ben_IE
dc.subjectCOLORECTAL-CANCERen_IE
dc.subjectMICROSATELLITE INSTABILITYen_IE
dc.subjectGRANZYME-Ben_IE
dc.subjectIKK-BETAen_IE
dc.subjectINFLAMMATIONen_IE
dc.subjectTUMORSen_IE
dc.subjectEVASIONen_IE
dc.subjectLIGANDen_IE
dc.titleStromal cell PD-L1iInhibits CD8(+) T-cell antitumor immune responses and promotes colon canceren_IE
dc.typeArticleen_IE
dc.date.updated2019-08-27T08:19:09Z
dc.identifier.doi10.1158/2326-6066.CIR-17-0443
dc.local.publishedsourcehttps://dx.doi.org/10.1158/2326-6066.CIR-17-0443en_IE
dc.description.peer-reviewedpeer-reviewed
dc.contributor.funderScience Foundation Irelanden_IE
dc.contributor.funderIrish Cancer Societyen_IE
dc.contributor.funderIrish Research Councilen_IE
dc.description.embargo2019-11-01
dc.internal.rssid15356016
dc.local.contactAideen Ryan, School Of Medicine, Nui Galway. Email: aideen.ryan@nuigalway.ie
dc.local.copyrightcheckedYes
dc.local.versionACCEPTED
dcterms.projectinfo:eu-repo/grantAgreement/SFI/SFI Starting Investigator Research Grant (SIRG)/15/SIRG/3456/IE/'RESTRAIN' Investigation of tumour stromal interactions in metastatic colon cancer for the identification of novel immuno-therapeutic targets/en_IE
dcterms.projectinfo:eu-repo/grantAgreement/SFI/SFI Investigator Programme/12/IA/1624/IE/Novel therapeutic approaches to improve corneal allograft survival by cell and gene therapy and insights into the mechanism of action/en_IE
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