Summary

Immunotherapy has been a major breakthrough in treating cancer but there is gathering evidence that the liver is proving a major barrier to the success of these therapies. This needs to be urgently resolved because primary liver cancer is rising rapidly throughout the world and additionally the liver is one of the commonest sites for spread of other tumours.

The cancer-killing cells of the immune system are known as T cells and they have thecapability to travel along our blood vessels to get to the location of the cancer todirectly kill tumour cells. A major step involves the movement of the T cell across the blood vessel wall and into the tumour. The liver has very specialised blood vessels which are lined by unique endothelial cells termed sinusoidal endothelial cells. There is gathering evidence that they contribute to protecting cancers from eradication by T cells, but the mechanisms are still poorly understood. To test new treatments that could improve outcomes from immunotherapy, we need models which reflect more accurately the liver environment in patients.

Through our access to human liver tissue, we can isolate liver endothelial cells and grow them in the laboratory. In this project, we aim to use the liver-on-a-chip to set up a model which reflects the blood vessels of the liver, combining the growth of endothelial cells and matrices that are found in the liver. We will then test if we can study how T cells interact with these liver blood vessels by perfusing them into the chip. By visualising how the T cells interact with liver endothelium we can identify and study the key molecules which control the movement of T cells, and subsequently test new drugs which could enhance T cells migrating to the tumour. The aim is to identify new treatments that could overcome the current resistance to immune therapies that we are currently seeing within the liver.