Natural killer cells in immunosurveillance for MASLD-HCC

MASLD (metabolic dysfunction associated steatotic liver disease) previously known as non-alcoholic fatty liver disease, is a rapidly increasing cause of chronic liver disease worldwide. It is strongly associated with the metabolic syndrome, which encompasses insulin resistance, obesity, hypertension and dyslipidaemia. A key complication of this condition is the development of hepatocellular carcinoma (HCC), which represents 80% of all liver cancers. Primary liver cancer is the fifth most frequently occurring cancer in the world and the second most common cause of cancer mortality (1). In 30-50% of individuals MASLD-HCC arises in a non-cirrhotic liver (2–4), suggesting that there is a specific dysfunction of immune surveillance in MASLD. I hypothesize that in MASLD NK cells are dysfunctional and this leads to reduced tumour immunosurveillance. The immune system has a key role in controlling tumour development. An important member of the immune system are natural killer (NK) cells, which can respond to abnormal cells by either direct killing or recruiting adaptive immune cells to the tumour. They express a variety of cell surface receptors governing their response to surrounding cells and so can recognise HCC cells through multiple mechanisms. Previous work in the Khakoo group has identified that the family of NK receptors called killer cell immunoglobulin-like receptors (KIR) recognise peptides presented by HLA class and this leads to activation of NK cells and lysis of target cells (5). Additionally HLA class I (HLA-E) is recognised by NKG2C and can lead to NK cell activation. However, there is limited understanding of how NK cells may function in the setting of MASLD-HCC. Studies have shown that NK cells in obesity (which is closely associated with MASLD) are impaired in their ability to respond to abnormal cells (6). I therefore aim to investigate the function of NK cells in MASLD and MASLD-HCC, and in particular how receptors for HLA class I impact the ability of NK cells to respond to cancer. My preliminary work has identified that the activating NK cell receptor NKG2C is significantly increased in patients with MASLD compared to healthy controls. Conversely, in patients with more advanced liver disease expression of NKG2C is reduced. NKG2C+ve cells can have enhanced anti-tumour activity and are associated with clonal expansions of inhibitory KIR-expressing NK cells (7). My hypothesis is that NKG2C marks a subpopulation of NK cells important for the immune response to HCC. The aims and objectives are to: Compare the expression of a panel of activating and inhibitory NK cell receptors on NK cells from patients with MASLD, MASLD-HCC and healthy controls, focusing on the differences between NKG2C+ve and NKG2C-ve populations Identify key activating and inhibitory NK cell receptor:ligand interactions between MASLD NK cells and HCC using a panel of HCC cell lines Test the relevance of these interactions using co-culture with patient derived HCC organoids. This work will identify novel mechanisms by which MASLD NK cells are activated or inhibited by HCC, and their potential for treatment by immunotherapy.