The role of inhibitory receptors in human NK cell function for immunotherapy

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BACKGROUNDNatural Killer (NK) cells are innate effector lymphocytes that play a crucial role in viral infections and tumour immunosurveillance. NK cells directly kill target cells by releasing cytotoxic granules (e.g. granzyme B) or activating other arms of the immune system by producing a variety of cytokines and chemokines (e.g. IFN). NK cell activation is driven by multiple activatory cell surface receptors that sense an aberrant or stressful environment. Activation is also modulated by multiple inhibitory receptors.PD-1 and CTLA-4 are two inhibitory receptors, also known as immune checkpoint receptors, which have previously been identified in T cells. Upon ligand binding, these receptors reduce immune cell activation and proliferation, a process which is often hijacked by cancer cells to evade the immune system. Therefore, immune checkpoint inhibitors have been intensively researched in the context of T cells and are currently used to treat several cancers.Recent evidence suggests that PD-1 blockade therapies remain efficient even for MHC-deficient tumours, which sheds light on the importance of inhibitory receptors on NK cells. Moreover, high PD-1 cell surface expression on NK cells was observed in ovarian cancer patients, associated with poor disease prognosis. CTLA-4 has been identified on mice NK cells, but determination of its role in human NK cell activity requires further investigation. AIM OF PHD PROJECTFirstly, to generate human NK cells lacking PD-1 and CTLA-4, using lentiviral-delivered CRISPR/Cas9 genome editing methods, in order to study the effect on NK cell biology. This will then include NK cell cytotoxicity studies against a variety of target cells, and cytokine production studies upon NK cell activation. Further characterisation would involve looking at individual signalling pathways and transcriptomics. Furthermore, these modified NK cells will be tested for their enhanced function in cancer immunotherapy.