Sabry, M; (2014) Human natural killer cell responses to tumour-priming. Doctoral thesis , UCL (University College London).

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Abstract

As one of the central components of host anti-tumour immunity, natural killer (NK) cells exert cellular cytotoxicity against tumour cells and secrete a milieu of immunoregulatory cytokines to inhibit tumour progression. NK cell-mediated cytotoxicity requires successful progression through discrete activation events that begin with NK cell adhesion to a target cell and culminate in the polarized release of cytotoxic granules into the immunological synapse. These activation events are tightly regulated by a complex array of signalling molecules, the engagement of which by ligands on target cells can determine susceptibility to NK cell-mediated killing. Resistance to NK cell cytotoxicity can be attributable to a deficiency in any of the signalling requirements for the events leading to granule exocytosis. Tumour resistance to NK cell lysis may be overcome by priming of NK cells with cytokines or by binding of NK cell activating receptors to ligands expressed on target cells. Here, the activation profiles of normal, freshly isolated human peripheral blood NK cells upon tumour-priming with the NK-resistant leukemic cell line, CTV-1 are defined, and candidate NK cell receptors involved in the delivery of the tumour-priming signal are identified. Results from this study demonstrate that NK cell responses to tumour-priming are distinct from those induced by the gold standard in immunotherapy, cytokine-priming. Tumour-priming of NK cells resulted in a significant downregulation of various activating NK cell receptors including CD16, NKp46, NK group 2, member D (NKG2D), and intracellular adhesion molecule (ICAM)-1. Tumour-primed NK cells (TpNKs) also exhibited a strong pro-inflammatory profile marked by ample secretion of macrophage inflammatory protein (MIP)-1α, MIP-1β, regulated on activation normal T cell expressed and secreted (RANTES), tumour necrosis factor (TNF)-α and interferon (IFN) -γ after short incubations with CTV-1. Their secretory profiles were distinct from the profiles of NK cells stimulated with exogenous cytokines or the NK-sensitive target cell line, K562. Collectively, data from this study demonstrates that NK cell responses can differ according to the type of stimulus, as well as the ligand combination presented by the target cell. The co-engagement of NK cell receptors LFA-1 and CD2 by their respective ligands on CTV-1 cells, ICAM-1 and CD15, seems to play an important role in the delivery of the tumour- priming signal.

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