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Cancer Immunology Research

Cancer Immunology is one of the most exciting and productive areas of biomedical research since the discovery of the ‘checkpoint inhibitors’ that are revolutionising cancer treatment by successfully manipulating the immune system.

The human immune response to malignancy has been a research focus for the COF group for almost three decades. In 1986, while working on the lymphoid mediated malignant condition in the intestine associated with coeliac disease, we renamed it Enteropathy Associated T cell Lymphoma or EATL (1) a name that has ‘stuck’. Since then, our group has collaborated with scientists, clinicians and surgeons in Ireland and abroad to characterize resident anti-tumour lymphoid populations in the gut and other solid organs of the human body and to investigate their role in tumour surveillance. We 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 (2-13). We found similar populations of immune cells in human gut (14-17), bone marrow (18-19) and endometrium (20-23) where they appear to have important tumour surveillant activity as well as other functions. In 2009, we were the first to discover that human omentum is a rich site of anti-tumour immunity with the highest proportion invariant NKT cells in the human body (24). In collaboration with clinicians and surgeons from diverse specialties, we have been investigating how infectious (25-26), metabolic (27), environmental (28) and endocrinological (29-30) mediators might influence these tumour surveillant lymphoid populations.

A particularly novel concept being explored by our group is the possibility that tumour surveillant innate lymphoid populations might differentiate in specific organs (30-32). So far, we have demonstrated lymphoid progenitor cells with natural killer differentiation markers in human liver (33,34), gut (35) and uterus (36). The research group has shown a range of abnormalities in tissue resident anti tumour immune activities, including altered cytokine profiles (37-38), dysfunctional NKR+ lymphoid cells (39-41) and differential splicing patterns of CD1d (42 and ms in preparation). In collaboration with colleagues at 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

COF was on the Board of the Irish Cancer Society (ICS) from 2006-2012. During this time she was responsible for the introduction of the ICS Fellowship and Scholarship scheme and appointment of a Director of Research at ICS.

This work has been funded by grants from the Health Research Board, Science Foundation Ireland and St. Vincent's University Hospital Liver Trust.

Prof. O’Farrelly was a member of the winning team along with Mathematical Oncologist, Jake Scott MD PhD and led by Surgical Oncologist John Molyneux MD, at the Cancer Immunology Workshop at the NIH-Funded Moffitt Cancer Centre, FL, USA on November 8-13 2015. This workshop was attended by individuals with clinical, mathematical and immunological expertise who were asked to develop and implement a mathematical model focused on the role of the immune system in cancer progression and treatment. Using the combined skills of mathematical modelling together with clinical and immunological data this team developed three different models that led them to hypothesize that an optimal balance of lymphocyte populations in an in vitro assay, would yield clinically significant reactivity to sarcoma. The primary purpose of their winning project (which was awarded $50,000 in funding) is to identify the optimal meta-phenotype of the TIL (tumour infiltrating lymphocyte) subpopulations in order to develop meaningful cell therapy treatment for patients with advanced sarcoma.

Meet the Researcher: Sarah Whelan

Publications (primary papers and reviews) in Cancer Immunology Related Research

  1. C. O'Farrelly, C. Feighery, D.S. O'Briain, F. Stevens, C. Connolly, C. McCarthy, D.G. Weir.  Humoral response to wheat protein in patients with coeliac disease and enteropathy associated T cell lymphoma. Br Med J 1986;293:908-910. PMID3094712.
  2. C O'Farrelly. Innate Immune Cells in the Liver. Encyclopedia of Medical Immunology. 2014, pp570-579.
  3. Nemeth E, Baird AW, O'Farrelly C. Microanatomy of the liver immune system. Semin Immunopathol. 2009 Jul 29.
  4. Canning C, O'Brien M, Hegarty J, O'Farrelly C. Liver Immunity and Tumour Surveillance. Immunology Letters 2006; 107(2): 83 – 86.
  5. O'Farrelly & D. G. Doherty. Innate Immune Mechanisms in the Liver C. In ‘Liver Immunology 2nd Edition’ 2006 (Eds Manns, Vierling & Gershwin)
  6. F. Smith, L. Golden-Mason, T. Deignan, S. Norris, N.Nolan, O.Traynor, G.McEntee, J.Hegarty*, C.O'Farrelly*. Localisation of T and B lymphocytes in histologically normal adult human donor liver J Hepato-Gastro 2003; Sep-Oct:50(53):1311-5 PMID 14571725.
  7. M. Curry, S. Norris, L. Golden-Mason, D. Doherty, T. Deignan, C. Collins, O. Traynor, G. McEntee, J. Hegarty*, C. O'Farrelly*. Isolation of lymphocytes from normal adult human liver suitable for phenotypic and functional characterisation. J Immunol Methods 2000;242:21-31. PMID 10986386.
  8. D.G. Doherty, C. O'Farrelly. Lymphoid Repertoires in Healthy Liver. In ‘Liver Immunology’ 2002 (Eds Michael Manns, Eric Gershwin) pp 31-46. Hanley & Belfus, Inc. Philadelphia.
  9. D. Doherty, C. O'Farrelly. Innate and Adaptive Lymphocytes in Human Liver. Immunol Rev 2000;174:5-20.
  10. C. O'Farrelly, N. Crispe. Prometheus through the looking glass: reflections on the hepatic immune system. Immunol Today 1999;20:394-398.
  11. D. Doherty, S. Norris, L. Madrigal-Estebas, G. McEntee, O. Traynor, J. Hegarty, C. O'Farrelly. The human liver contains multiple populations of NK cells, T cells and CD3+CD56+ natural T cells with distinct cytotoxic activities and Th1, Th2 and Th0 cytokine secretion patterns. J Immunol 1999;163:2314-2321. PMID 10438977.
  12. S. Norris, D. Doherty, C. Collins, G. McEntee, O. Traynor, J. Hegarty, C. O'Farrelly.  Natural T cells in the human liver: cytotoxic lymphocytes with dual T cell and natural killer cell phenotype and function are phenotypically heterogenous and include Valpha24-JalphaQ and gammadelta T cell receptor bearing cells. Hum Immunol 1999;60:20-31. PMID 9952024.
  13. S. Norris, C. Collins, D. Doherty, F. Smith, G. McEntee, O. Traynor, N. Nolan, J. Hegarty, C. O'Farrelly.  Resident human hepatic lymphocytes are phenotypically different from circulating lymphocytes. J Hepatol 1998;28:84-90. PMID 9537869.
  14. J. O'Keeffe, D. Doherty, T. Kenna, K. Sheahan, D. O'Donoghue, J. Hyland, C. O'Farrelly. Diverse populations of T cells with NK cell receptors accumulate in the human intestine in health and in colorectal cancer. Eur J Immunol 2004 Aug;34(8):2110-9 PMID 15259008.
  15. Abuzakouk M, Carton J, Feighery C, O'Donoghue DP, Weir DG, O'Farrelly C. CD4+ CD8+ and CD8 alpha+ beta- T lymphocytes in human small intestinal lamina propria. Eur J Gastroenterol Hepatol. 1998 Apr;10(4):325-9. PMID 9855049.
  16. J. McDevitt, C. Feighery, C. O'Farrelly, G. Martin, D.G. Weir, D.K. Kelleher.  Effects of tumour necrosis factor-a on BrdU incorporation in cultured human enterocytes. Med Inflamm 1995;4:31-37.
  17. S. Lynch, D. Kelleher, C. Feighery, D. Weir, C. O'Farrelly. Flow cytometric analysis of intraepithelial lymphocytes from human small intestinal biopsies reveals populations of CD4+CD8+ and CD8CD8[alpha][alpha]+cells. Eur J Gastroenterol Hepatol 1993;5:907-912.
  18. J. Dean, D. McCarthy, M.Lawler, D.G. Doherty, C. O'Farrelly*, L. Golden-Mason* Characterisation of NKR+T-cell subsets in human bone marrow: implications for immunosurveillance of neoplasia. Clin Immunol 2005 Jan;114(1):42-51 PMID 15596408.
  19. J. Dean, D. McCarthy, L. Golden-Mason, C. O'Farrelly Trephine biopsies are enriched for activated T/NK cells and cytotoxic T cells. Immunol Letters 2005 Jun15;99(1):94-102 PMID 15894117.
  20. McMenamin M, Lysakova-Devine T, Wingfield M, O'Herlihy C, O'Farrelly C. Endometrial aspiration biopsy: a non-invasive method of obtaining functional lymphoid progenitor cells and mature natural killer cells. Reprod Biomed Online. 2012 Sep;25(3):322-8. doi: 10.1016/j.rbmo.2012.05.001. Epub 2012 May 23.
  21. L. Flynn, B. Byrne, J. Carton, P. Kelehan, C. O'Herlihy, C. O'Farrelly. Menstrual cycle dependent fluctuations in NK and T-lymphocyte subsets from non-pregnant human endometrium. Am J Reprod Immunol 2000;43:209-217. PMID10836250.
  22. L. Flynn, J. Carton, B. Byrne, P. Kelehan. C. O'Herlihy, C. O'Farrelly. Optimisation of a technique for isolating lymphocyte subsets from human endometrium. Immunol Invest 1999;28:235-246. PMID 10454001.
  23. McGrath E, Ryan EJ, Lynch L, Golden-Mason L, Mooney E, Eogan M, O'Herlihy C, O'Farrelly C.  Changes in endometrial natural killer cell expression of CD94, CD158a and CD158b are associated with infertility.  Am J Reprod Immunol. 2009 Apr;61(4):265-76. PMID: 19260857
  24. Lynch, L, O'Shea, D, Winter, D, Geoghegan, J, Doherty, D and O'Farrelly, C (2009). Invariant NKT cells and CD1d-positive cells amass in human omentum and are depleted in patients with cancer and obesity.  Eur. J. Immunol. 2009 Jul;39(7):1893-901.
  25. Golden-Mason L, Madrigal-Estebas L, McGrath E, Conroy MJ, Ryan EJ, Hegarty JE, O'Farrelly C, Doherty DG. Altered natural killer cell subset distributions in resolved and persistent hepatitis C virus infection following single source exposure. Gut. 2008 Aug;57(8):1121-8. Epub 2008 Mar 27. PMID: 18372499 [PubMed - indexed for MEDLINE]
  26. T. Deignan, M.P. Curry, D.G. Doherty, L. Golden-Mason, Y. Volkov, S. Norris, N. Nolan, O. Traynor, G. McEntee, J.E. Hegarty*, C. O'Farrelly*. Decrease in hepatic CD56+ T cells and Va24+ natural killer T cells in chronic Hepatitis C viral infection. J Hepatol 2002; 37:101-8 PMID 12076868.
  27. O'Shea D, Cawood TJ, O'Farrelly C, Lynch L.  Natural killer cells in obesity: impaired function and increased susceptibility to the effects of cigarette smoke. PLoS One. 2010 Jan 25;5(1):e8660.PMID: 20107494
  28. M. Garland, E. Lavelle, D. Doherty, L. Golden-Mason, P. Fitzpatrick, A. Hill, N. Walsh, C.O'Farrelly. Cortisol does not mediate the suppressive effects of psychiatric morbidity on natural killer cell activity: a cross-sectional study of patients with early breast cancer.  Psychol Medicine 2004 34, 481-490 PMID 15259833.
  29. M. Garland, D. Doherty, L. Golden-Mason, P. Fitzpatrick, N. Walsh, C. O'Farrelly. Stress-related hormonal suppression of natural killer activity does not show menstrual cycle variations: implications for timing of surgery for breast cancer. Anti-Cancer Res.2003 May-Jun;23(3B):2531-5 PMID 12894537.
  30. Lysakova-Devine T, O'Farrelly C. Tissue-specific NK cell populations and their origin. J Leukoc Biol. 2014 Dec;96(6):981-90. doi: 10.1189/jlb.1RU0514-241R. Epub 2014 Sep 22. Review.
  31. L. Golden Mason, C. O'Farrelly. Having it all? Stem Cells, Haematopoiesis and Lymphopoiesis in Adult human Liver. Immunol Cell Biol 2002;80:45-51. PMID11869362.
  32. C.O'Farrelly, A.J. Strain, H. A. Crosby, J.E. Hegarty, L. Golden-Mason Human Hepatic Stem Cells – Potential for the Future In “Falk Symposium 135 – Immunological Diseases of Liver and Gut” (Eds M. Lukas, M.P. Manns, J. Spicak, E.F. Strange Kluwer Academic Publishers & Falk Foundation 2004) pp144-151
  33. O.M. Crosbie, M. Reynolds, G. McEntee, O. Traynor, J. Hegarty, C. O'Farrelly. In vitro evidence for the presence of hematopoietic stem cells in the adult human liver. Hepatology 1999;29:1193-1198. PMID 10094964.
  34. L. Golden-Mason, M. Curry, N. Nolan, O. Traynor, G. McEntee, J. Kelly, J. Hegarty*, C. O'Farrelly*. Differential expression of lymphoid and myeloid markers on differentiating hematopoietic stem cells in normal and tumor bearing adult human liver. Hepatology 2000;31:1251-1256. PMID 10827150
  35. L. Lynch, D.O'Donoghue, J. Dean, J. O'Sullivan, C. O'Farrelly*, L. Golden-Mason Detection and characterisation of haematopoietic stem cells in the adult human small intestine * J Immunol 2006 May 1; 176 (9): 5199-5204.PMID 16621984.
  36. L.Lynch, L. Golden-Mason, M.Eogan, C.O'Herlihy, C.O'Farrelly Cells with haematopoietic stem cell phenotype in adult human endometrium: relevance to infertility? Human Reproduction 2007; 22:919-926 PMID 17208945.
  37. AM Kelly, L. Golden-Mason, O. Traynor , J. Geoghegan, G. McEntee, J. Hegarty*, C. O'Farrelly* Changes in hepatic immunoregulatory cytokines in patients with metastatic colorectal carcinoma: implications for hepatic anti-tumour immunity Cytokine 35(2006) 171-179 PMID 16971136.
  38. A. Kelly, L.Golden-Mason,G. McEntee, O. Traynor, J.Hegarty*, D.Doherty*, C. O'Farrelly*. Interleukin 12 (IL-12) is increased in tumour-bearing liver and expands CD8(+) and CD56(+) T cells in vitro but not in vivo. Cytokine 2004 Mar 21;25(6):273-82 PMID 15036243.
  39. T. Kenna, L. Golden-Mason, S. Norris, J.E. Hegarty*, C. O'Farrelly*, D. Doherty* Distinct subpopulations of γδ T cells are present in normal and tumor-bearing human liver. Clin Immunol 2004 Oct;113(1):56-63 PMID 15380530.
  40. T. Kenna, L. Golden-Mason, SA Porcelli, Y. Koezuka, JE Hegarty*, C. O'Farrelly*, DG Doherty* NKT cells from normal and tumor-bearing human livers are phenotypically and functionally distinct from murine NKT cells. J Immunol 2003 Aug 15;171(4):1775-9. PMID 12902477.
  41. 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.
  42. Kenna T, O'Brien M, Hogan AE, Exley M, Porcelli S, Hegarty J*, O'Farrelly C*, Doherty DG*.  CD1 expression and CD1-restricted T cell activity in normal and tumor-bearing liver. Cancer Immunol Immunother 2006 Aug PMID 16924493

* These authors contributed equally to the direction of this study