Department of Medicine

Biography

Research Interests

Tumor-induced immune suppression is a fundamental problem in cancer biology and immunotherapy. During carcinogenesis, tumors develop multiple mechanisms to evade the anti-tumor immune response. We and others have shown that upregulation of Fas ligand (FasL/CD95L) expression may represent one such mechanism. FasL is a transmembrane glycoprotein belonging to the tumor necrosis factor superfamily that can trigger apoptotic cell death following ligation to its receptor, Fas (CD95/APO-1). Fas/FasL interactions play an important role in regulating immune homeostasis and in the maintenance of immune privilege in sites such as the eye and testis. However, we have shown that human cancers may also express FasL, which is associated with apoptosis of tumor-infiltrating lymphocytes and immune suppression. Also, inhibition of FasL expression in mouse colon tumor cells results in reduced tumor development and an improved anti-tumor immune challenge in vivo. These studies suggest that FasL expression by tumor cells may represent an important mechanism utilised by tumors to subvert the immune system and suppress the anti-tumor immune response. This is referred to as the ?Fas counterattack?. We are currently focusing on the mechanisms by which FasL expression aids in tumor immune evasion. Also, since little is known about the signals that induce this upregulation of FasL in cancer, we are also investigating the signal transduction events underlying FasL expression in cancer, since identifying the signalling pathway(s) involved may reveal potential molecular targets for cancer prevention and treatment.

Research is supported by funding from:

Health Research Board

Awards

St. Luke?s Young Investigator Award, Royal Academy of Medicine in Ireland, 2006.

Travel Scholarship from Cold Spring Harbour Laboratory to attend course on Immunocytochemistry, In situ Hybridisation and Live Cell Imaging, 2001.

Poster of Distinction Award, American Gastroenterology Association (AGA), Digestive Disease Week, Atlanta, 2001.

First Prize Scientific Poster Presentation (Pfizer Medal), Annual Medical Research Day, University Hospital Cork, 2001.

Student Abstract Prize, AGA, Digestive Disease Week, San Diego, CA, 2000.

First Prize Scientific Poster Presentation (Pfizer Medal) (co-author), Annual Medical Research Day, University Hospital Cork, 1999.

Publications

Ryan AE , Shanahan F, O'Connell J, Houston A. 2006. Fas ligand promotes tumor immune evasion of colon cancer in vivo. Cell Cycle 5(3):246-9.

Busteed S, Bennett MW, Molloy C, Houston A, Stone MA, Shanahan F, Molloy MG, O?Connell J. 2006. Bcl-XL expression in vivo in Rheumatoid Synovium. Clin Rheumatol (epub ahead of print).

Ryan AE, Lane S, Shanahan F, O'Connell J, Houston A. 2006. Fas ligand expression in human and mouse cancer cell lines; a caveat on over-reliance on mRNA data. J Carcinog Feb 2;5(1):5 (epub ahead of print).

Ryan AE, Shanahan F, O'Connell J, Houston AM. 2005. Addressing the "Fas counterattack" controversy: Blocking Fas ligand expression suppresses tumor immune evasion of colon cancer in vivo. Cancer Res 65:9817-23.

Houston A and O?Connell J. 2004. The Fas signalling pathway and its role in the pathogenesis of cancer. Current Opinion in Pharmacology 4:321-6.

Houston A, Bennett MW, O?Sullivan GC, Shanahan F, O?Connell J. 2003. Fas ligand mediates immune privilege and not inflammation in human colon cancer, irrespective of TGF- b expression. British Journal of Cancer 89:1345-1351.

Houston A, Waldron-Lynch FD, Bennett  MW, Roche D, O?Sullivan GC, Shanahan F, O?Connell J. 2003. Fas ligand expressed in colon cancer is not associated with increased apoptosis of tumor cells in vivo. International Journal of Cancer 107:209-214.

O?Connell J, Houston A, Nally K, Bennett MW, Shanahan F. 2002. Rapid development of a quantitative-competitive (qc) RT-PCR assay using a composite primer approach. Methods in Molecular Biology 193:93-102.

O?Connell J, Houston A, Bennett MW, O?Sullivan GC, Shanahan F. 2001. Immune privilege or inflammation? Insights into the Fas ligand enigma. Nature Medicine 7:271-274.

Bennett MW, O?Connell J, Houston A, Kelly J, O?Sullivan GC, Collins JK, Shanahan F. 2001. Fas ligand upregulation is an early event in colonic carcinogenesis. Journal of Clinical Pathology 54:598-604.

O?Connell J, Bennett MW, Nally K, Houston A, O?Sullivan GC, Collins JK, Shanahan F. 2000. Altered mechanisms of apoptosis in colon cancer: Fas resistance and counterattack in the tumor-immune conflict. Annals of New York Academy of Sciences 910:178-195.