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Marshaling NK-cells in the fight against blood cancers: a novel approach (2016)

Abstract:
Natural killer (NK)-cells are immune cells that lyse tumour cells without previous sensitization. New developments have led to a resurgence in interest in NK-cells in cancer. However, the underlying molecular mechanisms controlling NK-cell effector function remain very poorly understood. In exciting preliminary data, we provide compelling evidence implicating a new pathway that is critical to NK-cell effector function. We propose to take this work forward within the context of Blood Cancers. Our over-arching hypothesis is that the Inositol Requiring 1 - X-Box Binding Protein 1 (IRE1-XBP1) pathway is a critical regulatory hub for human NK-cell mediated lysis and can be manipulated to enhance NK-cell mediated killing of blood cancers. Specific aims are: 1. To characterize molecular networks downstream of the IRE1-XBP1 pathway in NK-cells. 2. To modulate the NK-cell IRE1-XBP1 pathway to enhance the destruction of blood cancers. In Aim 1 we will characterize in detail the specific molecular components involved in NK-cell cytotoxicity. Our approach focuses on the development of a novel and integrated systems analysis to identify and manipulate molecular circuitries associated with anti-tumoural immunity. Findings will fundamentally advance the science underpinning NK-cell anti-tumoural function: knowledge that is currently largely missing. Our model will be the fulcrum of future efforts to define novel target genes to enhance NK-cell cytotoxicity via the IRE1-XBP1 pathway, paving the way for highly-specific molecular agents so as to minimize off-target effects. Aim 2 will pragmatically focus on modulating the IRE1-XBP1 pathway using an IRE1-activator, to enhance NK-cell cytotoxicity, and to test for synergy with emerging immunotherapeutics that show promising activity in the field of blood cancers. Future strategies to modulate the pathway might include small molecules and/or gene interference. This can lead to new NK-cell based i...
Grant type:
PA Research Foundation NHMRC Near Miss Grant
Researchers:
Funded by:
PA Research Foundation