(1)Understanding the molecular role of NKG2D ligands in lymphoid stress recognition in cancer AND (2)Investigating neuroblastoma mediated immunosuppression

Hunter, Stuart (2014). (1)Understanding the molecular role of NKG2D ligands in lymphoid stress recognition in cancer AND (2)Investigating neuroblastoma mediated immunosuppression. University of Birmingham. M.Res.

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Abstract

Neuroblastoma, the most common extracranial solid tumour in children, has a long term survival rate of 45% but a very poor outcome in high-risk categorised patients, despite aggressive current therapies. In order to develop more effective immunotherapies, it is critical that we understand the immune microenvironment fostered by neuroblastoma tumours. We investigated potential mechanisms employed by neuroblastoma in suppression of the host's immune response. Using neuroblastoma-derived cell lines, we established that neuroblastoma is capable of suppressing allogeneic T cell proliferation in vitro, and that this suppression is not dependent on cell: cell contact. Active Arginase II is present in suppressive cell lines, and inhibition of this enzyme restored T cell proliferation, suggesting for the first time enhanced arginine metabolism as a mechanism of immunosuppression in neuroblastoma. We then established that neuroblastoma-derived cell lines are capable of activating monocytes to CD68+ macrophages, and that these macrophages also suppressed T cell proliferation. Finally, using biopsied tumour material from neuroblastoma patients, we established arginasedependent suppression ofT cell proliferation and macrophage activation by neuroblastoma ex vivo, confirming the physiological relevance of the cell line data. These results supp01t the hypothesis that neuroblastoma creates an immunosuppressive microenvironment that may enhance disease progression.

Type of Work:

Thesis (Masters by Research > M.Res.)

Award Type:

Masters by Research > M.Res.

Supervisor(s):