Medical Biology - Theses
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ItemTargeting regulators of natural killer cell homeostasis in cancer immunotherapy( 2018)The detection of aberrant cells by natural killer (NK) cells is controlled by the integration of signals from activating and inhibitory receptors and from cytokines such as IL-15. The ability to recognise tumour cells in the absence of antigen presentation has garnered significant interest in NK cells as novel targets for immunotherapy development. However, successful developments in this area have led to limited success. This is, in part, due to the lack of understanding of the underlying mechanisms governing inhibitory and stimulatory pathways in NK cells. In this work, we aimed to identify the key regulator of NK cell proliferation in order to further our understanding of NK cell activity both in the steady-state and in the setting of inflammation. Here, we have identified cytokine-inducible SH2-containing protein (CIS, encoded by Cish) as a critical negative regulator of IL-15 signalling in NK cells. IL-15 is the main driver of NK cell proliferation, survival, differentiation and function, and thus a highly relevant checkpoint in NK cell homeostasis. We found Cish was rapidly induced in response to IL-15, and deletion of Cish rendered NK cells hypersensitive to IL-15, as evidenced by enhanced proliferation, survival, IFNγ production and cytotoxicity toward tumours, in vitro. This was associated with increased JAK-STAT signalling in Cish-deficient NK cells. Cish-deficient mice were resistant to melanoma, prostate and breast cancer metastasis in vivo, and this was intrinsic to NK cell activity, uncovering CIS as a potent intracellular checkpoint in NK cell-mediated tumour immunity. Under homeostatic conditions, phenotypic changes in NK cells lacking Cish were observed in vivo. This included an increase in terminally differentiated NK cells as well as increased expression of cell cycle markers, suggesting that under steady-state conditions, CIS also plays a role in maintaining IL-15 driven regulation of NK cells in vivo. Additionally, the changes observed in steady state Cish-deficient NK cells manifested in a lower activation threshold, evidenced by the redundancy of exogenous IL-15 to induce augmented production of inflammatory cytokines and cytotoxicity when stimulated ex vivo. These data suggest that Cish not only regulates NK cell responsiveness to IL-15, but may also play a role in maintaining an activation threshold, consequently regulating effector functions in vivo. Furthermore, inhibition of CIS was found to be conserved between human and mouse NK cells, emphasising its potential role as a novel immunotherapy target for the treatment of human cancer.