NATURAL KILLER CELL FUNCTIONS ARE IMPAIRED IN PATIENTS WITH NEUROBLASTOMA Sinad Keating1,2, Megan Dring1,2, Sinad Dunphy1,

Cormac Owens2, Anne OMeara2 and Clair Gardiner1 1 School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin. 2National Childrens Research Centre, Our Ladys Childrens Hospital, Crumlin, Dublin 12.

Background: While prognosis for Neuroblastoma (NB) patients presenting at <18 months is usually favourable, approximately 45% of patients present with high risk tumours where prognosis for survival is poor. Therefore, identifying factors involved in NB development and progression is important for understanding the molecular basis of the disease and the potential for the development of new therapeutic approaches. Natural killer (NK) cells play a key role in the immuno-surveillance of tumours and have been shown to kill both NB cell lines and primary tumour cells. Some of the receptor interactions involved in adult NK cell killing of NB cells have been identified. However, the expression of these receptors as well as the efficacy of NK cell function in NB patients is unknown. Methods: To investigate modulation of NK cell function in NB, we analysed surface expression of CD107a, a marker of NK cell degranulation, as well as intracellular IFN cytokine expression in NB patients. Surface expression of a panel of activatory NK cell receptors was also examined to determine if expression of key triggering receptors correlated with NK cell activity in NB. Results: While expression of the activatory receptors investigated was unaltered, NK cellmediated induction of IFN and cytolytic activity was substantially impaired in NB. Comparison of important NK cell regulatory cytokines showed that IL12/IL15mediated activation of NK cell function was more dramatically reduced than IL2induced NK cell functions. Conclusion: Impaired NK cell functions in NB may represent an evasion mechanism to facilitate disease progression. Our data showing more severe impairment of IL12/IL15mediated NK cell activation may have implications for immunotherapy regimes using IL12 that are currently being investigated in murine models for the treatment of NB.