Abstract
Oral 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.
Highlights
Even allowing for comparable tumour stages the prognosis for patients suffering from oesophageal and gastric cancer remains consistently and significantly poorer than for patients with distal gastrointestinal tract cancers, despite advances in diagnostic, surgical and adjuvant therapies [1,2]
It is likely that tumour Ags derived from tumour tissue shed into the intestine by foregut cancers would be processed by the gut associated lymphoid tissues (GALT), predominantly found in the proximal gastrointestinal tract, in a way reminiscent of Ags ingested by the mucosal immune system, creating a tumour Ag specific immune tolerance
There was a significant increase in CD4+CD25+ cells (p,0.022) following tumour administration versus phosphate buffered saline (PBS)
Summary
Even allowing for comparable tumour stages the prognosis for patients suffering from oesophageal and gastric cancer remains consistently and significantly poorer than for patients with distal gastrointestinal tract cancers, despite advances in diagnostic, surgical and adjuvant therapies [1,2]. It is likely that tumour Ags derived from tumour tissue shed into the intestine by foregut cancers would be processed by the gut associated lymphoid tissues (GALT), predominantly found in the proximal gastrointestinal tract, in a way reminiscent of Ags ingested by the mucosal immune system, creating a tumour Ag specific immune tolerance. In T cell receptor (TCR) transgenic mice, there was an increase in CD4+CD25+ cells in response to oral Ag administration. These Tregs were found to express CTLA-4 and foxp and to have a suppressive function in vitro. As tumours grow, there is a numerical increase in Tregs in the immune infiltrate with consequent local suppression of the antitumour immune responses. Antibody (Ab) mediated removal of these Tregs can unmasks natural tumour immune reactivity and this strategy has been shown to potentiate the immunotherapeutic destruction of experimental cancers [10,11,12]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
