Oral tolerance to cancer can be abrogated by T regulatory cell inhibition
AuthorsWhelan, Maria C.
Larkin, John O.
O'Sullivan, Gerald C.
MetadataShow full item record
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.
CitationWhelan, M.C., Casey, G., O. Larkin, J., Guinn, B.A., O’Sullivan, G.C., & Tangney, M. (2014) 'Oral tolerance to cancer can be abrogated by T regulatory cell inhibition.' PLoS ONE 9(5): e97602
PubMed Central IDPMC4022586
SponsorsThis work was funded through a research grant to GOS and MT from Cancer Research Ireland (CRI06OSUG). MW was funded by a fellowship from the Royal College of Surgeons Edinburgh and the Royal College of Surgeons Ireland. The authors also acknowledge support from the Cork Cancer Research Centre.
The following license files are associated with this item:
- Effective immunotherapy of weakly immunogenic solid tumours using a combined immunogene therapy and regulatory T-cell inactivation.
- Authors: Whelan MC, Casey G, MacConmara M, Lederer JA, Soden D, Collins JK, Tangney M, O'Sullivan GC
- Issue date: 2010 Jul
- Combination of CTL-associated antigen-4 blockade and depletion of CD25 regulatory T cells enhance tumour immunity of dendritic cell-based vaccine in a mouse model of colon cancer.
- Authors: Saha A, Chatterjee SK
- Issue date: 2010 Feb
- Regional oral tolerance in transgenic 2C mice.
- Authors: Margenthaler JA, Flye MW
- Issue date: 2005 Aug
- Regulatory T cells are necessary for implantation and maintenance of early pregnancy but not late pregnancy in allogeneic mice.
- Authors: Shima T, Sasaki Y, Itoh M, Nakashima A, Ishii N, Sugamura K, Saito S
- Issue date: 2010 Jun
- Sublingual 'oral tolerance' induction with antigen conjugated to cholera toxin B subunit generates regulatory T cells that induce apoptosis and depletion of effector T cells.
- Authors: Sun JB, Czerkinsky C, Holmgren J
- Issue date: 2007 Aug-Sep