Improving outcomes for patients with hepatocellular carcinoma (HCC)

Hepatocellular carcinoma (HCC) is a cancer arising from the liver and the third commonest cause of death from cancer globally, with 906,000 new cases and 830,000 deaths in 2020 alone. Non-alcohol-related steatohepatitis ('NASH', fat within the liver causing dysfunction) is also becoming increasingly common, and HCC commonly occurs in patients with NASH. One requirement for the development of cancer (and HCC) is for tumour cells to gain the ability to 'hide' from the immune system. There is evidence that the immune system promotes survival and evolution of cancer by creating an ideal environment for tumour cells to grow (known as the tumour microenvironment). New treatments have been developed that 'switch on' the tumour immune system, resulting in immune-mediated killing of tumour cells. This is broadly known as 'immunotherapy' and has been particularly successful in treating patients with melanoma. However there is evidence that it may be less effective in patients with NASH for unknown reasons.

The best treatment for patients with HCC is surgery to either remove the HCC from the liver (liver resection) or a liver transplant (which removes the tumour and the whole diseased liver, replacing it with a liver usually from a deceased donor). However, in most patients, the HCC is too advanced for resection or transplantation, therefore the majority are treated with chemotherapy. Immunotherapies may help reduce the size and number of tumours in patients with advanced HCC, and allow more patients to undergo liver resection or transplantation.

I aim to experimentally recapitulate features of the human HCC tumour microenvironment using HCC cells obtained from patients (with permission) and grown on 'slices' of human liver tissue that have been treated with fat to cause NASH. Our research group has developed this model, which allows us to observe the impact different conditions have on the liver and tumour tissue, and model novel HCC treatments. I will use this model to observe how immune cells in the liver tissue interact with the tumour, and why these conditions make immunotherapy less effective. I also plan to find out what impact the presence of fat in the liver tissue has on immune cell functions and immunotherapy. I will investigate what effect liver resection has on tumour growth in the liver tissue left behind using a mouse model of HCC. Although liver resection removes the tumour, there may be more 'hidden' tumours in the liver tissue left behind that were not known about. Liver resection switches on growth signals, which may drive HCC growth as an unwanted side effect. Determining whether this happens may help us understand why some patients develop disease recurrence very early after resection. Finally I will determine what effect immunotherapy has on the ability of the liver to heal after liver resection, and how it impacts the behaviour of immune cells in tumour tissue left behind in the remnant liver.

This PhD project will establish a strong foundation for my future career as an academic liver surgeon focussed on HCC research, and provide insights that will help cancer researchers design improved HCC immunotherapies that reduce the risk of tumour recurrence. The research will have wider applications, as surgery is used for other types of cancer (in the liver and other organs), and will develop our understanding of how the immune system affects cancer behaviour/growth in general.

The majority of patients with HCC present with advanced disease (multifocal/bilobar), where resection cannot be safely performed (due to inadequate future liver remnant and cirrhosis) and liver transplantation is not an option due to strict listing criteria. Neoadjuvant immunotherapy may downstage advanced HCC, facilitating resection/transplantation. However, the impact of neoadjuvant immunotherapy on the regenerative processes is unknown, particularly in the context of MASH. Moreover, the risk of HCC recurrence following resection is very high due to the persisting disease microenvironment and/or small undetected cancerous lesions not seen on pre-operative imaging. The process of liver resection results in growth signals to drive the repair and regeneration of the liver tissue left behind. These signals could also be driving the growth of tumours that were not detected before resection, resulting in early 'recurrence'.

I will characterise the HCC tumour-microenvironment using patient-derived HCC tumour spheroids engrafted onto steatotic human precision-cut liver slices. I will also develop an HCC mouse model of liver resection to determine whether resection leads to proliferation of tumour cells in the remnant liver and immune evasion, driving early recurrence. Finally, I will determine the effect of neoadjuvant immunotherapy in treating bilobar HCC in a mouse to facilitate liver resection, and determine the effect on the regenerative process in the normal liver and tumour tissue. The insights obtained will help guide the development of future treatments through improving our understanding of the HCC immune system and its response to surgery. The findings will be generalisable to other cancers (in the liver and beyond) which share immune evasion as a hallmark of cancer development, particularly secondary metastatic liver tumours (e.g. colorectal, biliary tract cancers, and pancreatic).