Supervisor View Full Details

• cancer/oncology

• Medicine
• Public Health

• Immunology
• Oncology

We focus on the human immune response to malignancy and were amongst the first in the world to describe the human liver as a major organ of innate immunity populated with repertoires of natural killer and natural killer-like cells with potent anti-tumour activity. A particularly novel concept being explored by our group is the possibility that tumour surveillant innate lymphoid populations might differentiate in specific organs. So far, we have demonstrated lymphoid progenitor cells with natural killer differentiation markers in human liver, gut and uterus. The research group has shown a range of abnormalities in tissue resident anti tumour immune activities, including altered cytokine profiles, dysfunctional NKR+ lymphoid cells and differential splicing patterns of CD1d. In collaboration with St.James and St.Vincent?s Hospitals, we are exploiting these findings to develop new prognostic indicators and novel immunotherapies for patients with colorectal liver metastases .
S. Norris, D.G. Doherty, M. Curry, G. McEntee, O. Traynor, J.E. Hegarty, C. O?Farrelly. Selective reduction of natural killer cells and T cells expressing inhibitory receptors for MHC class 1 in the livers of patients with hepatic malignancy. Cancer Immunol Immunotherapy 2003; 52:53-58 PMID 12536240.
Harmon C, Robinson MW, Fahey R, Whelan S, Houlihan DD, Geoghegan J, O'Farrelly C. Tissue-resident Eomes(hi) T-bet(lo) CD56(bright) NK cells with reduced proinflammatory potential are enriched in the adult human liver. Eur J Immunol. 2016 Sep;46(9):2111-20. doi: 10.1002/eji.201646559.

Many patients with liver metastases have poor outcomes but there is no way of identifying these patients and currently available treatments are ineffective. Populations of tissue-resident Natural Killer (NK) cells in the liver normally provide successful anti-tumour surveillance. However, this surveillance function is compromised in patients with liver metastases. We hypothesise that the metabolic environment of metastatic liver changes the phenotype and cytotoxic capability of NK cells. We aim to determine how NK phenotype and metabolic function is influenced by the microenvironment of metastatic liver with a view to restoring normal NK activity with metabolic regulators. Clinical data on metastasis relapse and survival, alongside liver biopsy samples, will be collected from patients undergoing resection of liver metastasis and primary colorectal cancers in collaboration with the Liver Unit and Colorectal Cancer Group at St. Vincent?s University Hospital and surgeons at St.James's Hospital. The project aims to define the metabolome of metastatic liver and anticipate that specific metabolic signatures will predict patient outcomes. We aim to determine how liver metabolites altered during metastasis effect NK cell metabolic activity and cytotoxic function. Use of PCR gene expression arrays on tissue biopsies from patients with colorectal liver metastasis will investigate the metabolic changes within the immune suppressive tumour microenvironment and assess the relative contribution of host tissue-derived and tumour-derived metabolites. Flow cytometry will identify cell-surface markers on hepatic NK cells that are associated with metabolic dysfunction during colorectal liver metastasis. In vitro functional assays targeting colorectal cancer cell lines will assess the sensitivity of hepatic anti-tumour NK cells to changes in the metabolic microenvironment. The project will assess the ability of therapeutic drugs that regulate metabolism to boost or inhibit the anti-tumour functions of hepatic NK cells. Ultimately these studies will generate metabolic profiles which can be used to identify prognostic markers for colorectal liver metastasis in clinical cohorts.