Oral tolerance to cancer can be abrogated by T regulatory cell inhibition

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dc.contributor.authorWhelan, Maria C.
dc.contributor.authorCasey, Garrett
dc.contributor.authorLarkin, John O.
dc.contributor.authorGuinn, Barbara-Ann
dc.contributor.authorO'Sullivan, Gerald C.
dc.contributor.authorTangney, Mark
dc.contributor.funderCancer Research Ireland
dc.contributor.funderRoyal College of Surgeons of Edinburgh, United Kingdom
dc.contributor.funderRoyal College of Surgeons in Ireland
dc.contributor.funderCork Cancer Research Centre, College of Medicine and Health, University College Cork
dc.date.accessioned2016-02-17T11:44:40Z
dc.date.available2016-02-17T11:44:40Z
dc.date.issued2014
dc.description.abstractOral administration of tumour cells induces an immune hypo-responsiveness known as oral tolerance. We have previously shown that oral tolerance to a cancer is tumour antigen specific, non-cross-reactive and confers a tumour growth advantage. We investigated the utilisation of regulatory T cell (Treg) depletion on oral tolerance to a cancer and its ability to control tumour growth. Balb/C mice were gavage fed homogenised tumour tissue - JBS fibrosarcoma (to induce oral tolerance to a cancer), or PBS as control. Growth of subcutaneous JBS tumours were measured; splenic tissue excised and flow cytometry used to quantify and compare systemic Tregs and T effector (Teff) cell populations. Prior to and/or following tumour feeding, mice were intraperitoneally administered anti-CD25, to inactivate systemic Tregs, or given isotype antibody as a control. Mice which were orally tolerised prior to subcutaneous tumour induction, displayed significantly higher systemic Treg levels (14% vs 6%) and faster tumour growth rates than controls (p<0.05). Complete regression of tumours were only seen after Treg inactivation and occurred in all groups - this was not inhibited by tumour feeding. The cure rates for Treg inactivation were 60% during tolerisation, 75% during tumour growth and 100% during inactivation for both tolerisation and tumour growth. Depletion of Tregs gave rise to an increased number of Teff cells. Treg depletion post-tolerisation and post-tumour induction led to the complete regression of all tumours on tumour bearing mice. Oral administration of tumour tissue, confers a tumour growth advantage and is accompanied by an increase in systemic Treg levels. The administration of anti-CD25 Ab decreased Treg numbers and caused an increase in Teffs. Most notably Treg cell inhibition overcame established oral tolerance with consequent tumor regression, especially relevant to foregut cancers where oral tolerance is likely to be induced by the shedding of tumour tissue into the gut.en
dc.description.sponsorshipCancer Research Ireland (CRI06OSUG); Royal College of Surgeons of Edinburgh, United Kingdom (Fellowship); Royal College of Surgeons in Ireland (Fellowship)en
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.articleide97602
dc.identifier.citationWhelan MC, Casey G, Larkin JO, Guinn B-a, O'Sullivan GC, Tangney M (2014) Oral Tolerance to Cancer Can Be Abrogated by T Regulatory Cell Inhibition. PLoS ONE 9(5): e97602. doi:10.1371/journal.pone.0097602
dc.identifier.doi10.1371/journal.pone.0097602
dc.identifier.issn1932-6203
dc.identifier.issued5en
dc.identifier.journaltitlePLOS ONEen
dc.identifier.urihttps://hdl.handle.net/10468/2339
dc.identifier.volume9en
dc.language.isoenen
dc.publisherPublic Library of Scienceen
dc.rights© 2015 Whelan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are crediteden
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectImmune toleranceen
dc.subjectImmunotherapyen
dc.subjectEsophagealen
dc.subjectInductionen
dc.subjectSurvivalen
dc.titleOral tolerance to cancer can be abrogated by T regulatory cell inhibitionen
dc.typeArticle (peer-reviewed)en
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