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dc.contributor.authorO'Driscoll, Lorraine
dc.contributor.authorMartinez, Vanesa G.
dc.contributor.authorO'Neill, Sadhbh
dc.contributor.authorSalimu, Josephine
dc.contributor.authorBreslin, Susan
dc.contributor.authorClayton, Aled
dc.contributor.authorCrown, John
dc.date.accessioned2020-03-13T14:12:26Z
dc.date.available2020-03-13T14:12:26Z
dc.date.issued2017
dc.date.submitted2017en
dc.identifier.citationMartinez, V.G., O'Neill, S., Salimu, J., Breslin, S., Clayton, A., Crown, J. & O'Driscoll, L., Resistance to HER2-targeted anti-cancer drugs is associated with immune evasion in cancer cells and their derived extracellular vesicles, Oncoimmunology, 6, 12, 2017, 530 - 540en
dc.identifier.issn2162-4011
dc.identifier.otherY
dc.identifier.urihttps://www.tandfonline.com/doi/full/10.1080/2162402X.2017.1362530
dc.identifier.urihttp://hdl.handle.net/2262/91792
dc.descriptionPUBLISHEDen
dc.description.abstractNeuromedin U (NmU) -a neuropeptide belonging to the neuromedin family– plays a substantial role in HER2-positive breast cancer, correlating with increased aggressiveness, resistance to HER2-targeted therapies and overall significantly poorer outcome for patients. However, the mechanism through which it exerts these effects remains unclear. To elucidate this, initially we used HER2-positive breast cancer cells stably over-expressing NmU. These cells and their released extracellular vesicles (EVs) had increased amounts of the immunosuppressive cytokine TGFβ1 and the lymphocyte activation inhibitor PD-L1. Furthermore, these cells also showed enhanced resistance to antibody-dependent cell cytotoxicity (ADCC) mediated by trastuzumab, indicating a role of NmU in enhancing immune evasion. All these features were also found in HER2-targeted drug-resistant cells which we previously found to express higher levels of NmU than their drug-sensitive counterparts. Interestingly, EVs from drug-resistant cells were able to increase levels of TGFβ1 in drug-sensitive cells. In our neo-adjuvant clinical trial, TGFβ1 levels were significantly higher in EVs isolated from the serum of patients with HER2-overexpressing breast cancers who went on to not respond to HER2-targeted drug treatment, compared with those who experienced complete or partial response. Taken together, our results report a new mechanism-of-action for NmU in HER2-overexpressing breast cancer that enhances resistance to the anti-tumor immune response. Furthermore, EV levels of TGFβ1 correlating with patients' response versus resistance to HER2-targeted drugs suggests a potential use of EV-TGFβ1 as a minimally-invasive companion diagnostic for such treatment in breast cancer.en
dc.format.extent530en
dc.format.extent540en
dc.language.isoenen
dc.relation.ispartofseriesOncoimmunology;
dc.relation.ispartofseries6;
dc.relation.ispartofseries12;
dc.rightsYen
dc.subjectBiomarkeren
dc.subjectExtracellular vesiclesen
dc.subjectExosomesen
dc.subjectImmune evasionen
dc.subjectNeo-adjuvant clinical trialen
dc.subjectNeuromedin Uen
dc.titleResistance to HER2-targeted anti-cancer drugs is associated with immune evasion in cancer cells and their derived extracellular vesiclesen
dc.typeJournal Articleen
dc.type.supercollectionscholarly_publicationsen
dc.type.supercollectionrefereed_publicationsen
dc.identifier.peoplefinderurlhttp://people.tcd.ie/lodrisc
dc.identifier.rssinternalid180475
dc.identifier.doi10.1080/2162402x.2017.1362530
dc.rights.ecaccessrightsopenAccess
dc.subject.TCDThemeCanceren
dc.subject.TCDTagBREAST CANCERen
dc.identifier.orcid_id0000-0002-9860-8262


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