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Hepatocellular carcinoma (HCC) arises in the liver, is the fifth most common cancer worldwide and the third commonest cause of cancer death. On a worldwide basis it arises on the background of viral hepatitis, but its prevalence is increasing in the UK due to the rise in numbers of people with non-alcoholic fatty liver disease, which is associated with obesity. It remains difficult to treat, in part because it arises in livers that are usually damaged by cirrhosis, which means that chemotherapeutic agents are poorly tolerated by patients. Furthermore, patients present in advanced stages of disease beyond the time when curative surgical treatment is possible. The outlook for these patients is poor and therefore newer therapies are needed. Natural killer (NK) cells are cells of the innate immune system which have anti-cancer properties and the liver is an organ where NK cells accumulate. We therefore propose that NK cells are a potential therapeutic for HCC. NK cell targeting therapies are currently undergoing much investigation, but are often cumbersome and expensive. Our recent work has suggested that a novel therapeutic strategy involving vaccination, might be an option for developing better NK cell targeting strategies. We propose using a DNA vaccine that encodes a sequence for a protein that our previous work has shown is recognised by the NK cell receptor KIR2DS2. We will first optimise the procedure for delivering this DNA vaccine. The DNA vaccine will then be tested in preclinical models to determine their potential as therapeutics, focussing on HCC as the therapeutic target. As part of this project we will also test the novel concept that NK cells can recognise tumour antigens in a similar way to another immune cell, the cytotoxic T cell. These cells recognise small fragments of cellular proteins which are displayed on the cell surface by specialised proteins called MHC class I molecules, Our on-going work shows that one small peptide, derived from the protein XPO1, is a potential target for NK cells by binding MHC class I and KIR2DS2 and then activating NK cells. The XPO1 protein is upregulated in many cancers including hepatocellular carcinoma. We therefore consider that it provides a rationale for our NK cell therapy of HCC. We will perform in vitro and in vivo experiments to test the hypothesis that KIR2DS2+ NK cells recognise XPO1 as a tumour antigen. Our work tests a novel strategy for NK cell therapy, which has potential translational and clinical benefit for HCC, and for other cancers. We believe it would have wide applicability as both a monotherapy and in conjunction with currently available immunotherapeutic strategies.