Oral immune tolerance mediated by suppressor T cells may be responsible for the poorer prognosis of foregut cancers John Larkin, Mark Tangney, Chris Collins, Garrett Casey, Michael G. O’Brien, Declan Soden, Gerald C. O’Sullivan * Cork Cancer Research Centre, Leslie C. Quick Jnr. Laboratory, Mercy University Hospital, Cork, Ireland Received 1 September 2005; accepted 2 September 2005 Summary The poor prognosis of foregut cancers might, in part, be due to the immune tolerising effect of tumour antigens which are shed into the gastrointestinal tract and processed by the gut immune system. This would create a tumour specific tolerance without compromise of global immune functions. Experimental data shows that orally fed cancer tissue induces a non cross reactive attenuation of the cellular anti tumour host responses and confers a growth advantage specific to individual cancers. Although the cellular basis of such pro-tumourogenic responses has yet to be established, it is likely, based on studies of oral tolerance mechanisms, that recruitment of immune suppressive T cells (T regs ) may be responsible. Abrogation of oral immune tolerance to the tumour by immune based therapy could represent a significant advance in the management of upper gastrointestinal cancers.  c 2005 Elsevier Ltd. All rights reserved. Introduction/background Despite advances in therapy, when patients with similar stages of disease at the time of diagnosis are compared, those with cancer of the oesophagus and stomach have a poorer outcome than those with cancer of the rectum and colon [1–4]. Among the many variables that determine tumour growth rates and prognoses, differences in tumour immune responsiveness are likely to exist between foregut and other cancers. It is likely that tumour antigens derived from tumour tissue shed into the intestine by foregut cancers would be processed similarly to ingested antigens by the mucosal immune system, thus creating a tumour specific immune tolerance which would confer a growth and metastatic advantage to the growing cancer. Oral tolerance is a systemic antigen-specific hyporesponsiveness that occurs after oral antigen administration and has been demonstrated to be effective against potent immune and hypersensi- tivity responses. The concept of oral tolerance was validated in 1911, when HG Wells found that ovalbumin from hens’ eggs, when fed to guinea pigs, abrogated hypersensitivity responses to the injected protein [5]. Oral administration of anti- 0306-9877/$ - see front matter  c 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2005.09.021 * Corresponding author. Tel.: +353 21 493 5296. E-mail address: geraldc@iol.ie (G.C. O’Sullivan). Medical Hypotheses (2006) 66, 541–544 http://intl.elsevierhealth.com/journals/mehy