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dc.contributor.authorWilliams, Geoffrey Sen
dc.contributor.authorMistry, Binaen
dc.contributor.authorGuillard, Sandrineen
dc.contributor.authorUlrichsen, Jane Coatesen
dc.contributor.authorSandercock, Alan Men
dc.contributor.authorWang, Junen
dc.contributor.authorGonzález-Muñoz, Andreaen
dc.contributor.authorParmentier, Julieen
dc.contributor.authorBlack, Chelseaen
dc.contributor.authorSoden, Joen
dc.contributor.authorFreeth, Jimen
dc.contributor.authorJovanović, Jelenaen
dc.contributor.authorLeyland, Rebeccaen
dc.contributor.authorAl-Lamki, Rafiaen
dc.contributor.authorLeishman, Andrew Jen
dc.contributor.authorRust, Steven Jen
dc.contributor.authorStewart, Rossen
dc.contributor.authorJermutus, Lutzen
dc.contributor.authorBradley, Johnen
dc.contributor.authorBedian, Vaheen
dc.contributor.authorValge-Archer, Viiaen
dc.contributor.authorMinter, Ralphen
dc.contributor.authorWilkinson, Robert Wen
dc.date.accessioned2018-07-20T08:00:28Z
dc.date.available2018-07-20T08:00:28Z
dc.date.issued2016-10-18en
dc.identifier.issn1949-2553
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/278311
dc.description.abstractAntibodies that target cell-surface molecules on T cells can enhance anti-tumor immune responses, resulting in sustained immune-mediated control of cancer. We set out to find new cancer immunotherapy targets by phenotypic screening on human regulatory T (Treg) cells and report the discovery of novel activators of tumor necrosis factor receptor 2 (TNFR2) and a potential role for this target in immunotherapy. A diverse phage display library was screened to find antibody mimetics with preferential binding to Treg cells, the most Treg-selective of which were all, without exception, found to bind specifically to TNFR2. A subset of these TNFR2 binders were found to agonise the receptor, inducing iκ-B degradation and NF-κB pathway signalling in vitro. TNFR2 was found to be expressed by tumor-infiltrating Treg cells, and to a lesser extent Teff cells, from three lung cancer patients, and a similar pattern was also observed in mice implanted with CT26 syngeneic tumors. In such animals, TNFR2-specific agonists inhibited tumor growth, enhanced tumor infiltration by CD8+ T cells and increased CD8+ T cell IFN-γ synthesis. Together, these data indicate a novel mechanism for TNF-α-independent TNFR2 agonism in cancer immunotherapy, and demonstrate the utility of target-agnostic screening in highlighting important targets during drug discovery.
dc.description.sponsorshipGW, BM, SG, JC-U, AS, AG-M, CB, JJ, RL, AJL, SR, RS, LJ, VV-A, RM and RWW were funded by MedImmune; JP and VB were funded by AstraZeneca PLC; JW, RSA-L and JB were funded by NIHR Cambridge Biomedical Research Centre and Kidney Research UK; JS and JF were funded by Retrogenix Ltd.
dc.languageengen
dc.publisherImpact Journals
dc.rightsAttribution 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectTNFR2en
dc.subjectcancer immunotherapyen
dc.subjectdrug discoveryen
dc.subjectphenotypic screeningen
dc.subjectregulatory T cellen
dc.subjectAnimalsen
dc.subjectAntineoplastic Agentsen
dc.subjectCell Line, Tumoren
dc.subjectDrug Screening Assays, Antitumoren
dc.subjectFemaleen
dc.subjectHEK293 Cellsen
dc.subjectHumansen
dc.subjectImmunotherapyen
dc.subjectJurkat Cellsen
dc.subjectMice, Inbred BALB Cen
dc.subjectNF-kappa Ben
dc.subjectNeoplasmsen
dc.subjectNeoplasms, Experimentalen
dc.subjectPhenotypeen
dc.subjectReceptors, Tumor Necrosis Factor, Type IIen
dc.subjectSignal Transductionen
dc.subjectT-Lymphocytes, Regulatoryen
dc.titlePhenotypic screening reveals TNFR2 as a promising target for cancer immunotherapy.en
dc.typeArticle
prism.endingPage68291
prism.issueIdentifier42en
prism.publicationDate2016en
prism.publicationNameOncotargeten
prism.startingPage68278
prism.volume7en
dc.identifier.doi10.17863/CAM.24987
dcterms.dateAccepted2016-08-13en
rioxxterms.versionofrecord10.18632/oncotarget.11943en
rioxxterms.versionVoR*
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/en
rioxxterms.licenseref.startdate2016-10-18en
dc.contributor.orcidWang, Jun [0000-0003-3667-3760]
dc.contributor.orcidBradley, John [0000-0002-7774-8805]
dc.identifier.eissn1949-2553
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idKidney Research UK (SP/GW1/2012)
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (3819-1617-30)
cam.issuedOnline2016-09-10en
dc.identifier.urlhttp://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=11943&path%5B%5D=37807en


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