Modelling cargo loaded macrophage trafficking across liver endothelium: a new approach to drug delivery in liver cancer.

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Liver cancer also known as hepatocellular cancer(HCC) is one of the most lethal tumours in the world and cases are rising dramatically in the United Kingdom. Immunotherapy is one of the recent breakthroughs in treating this cancer and yet only 20% of patients show tumour response and therefore new approaches are urgently needed. To date, the focus of cancer therapy has been on T cells from the adaptive arm of the immune system but therapies focusing on monocytes/macrophages within the innate arm are less well developed. Monocytes are macrophage precursors that circulate in the blood and then migrate across endothelial cells into tissue and tumours and change into tissue resident macrophages. They have intrinsic properties that can profoundly change the tumour microenvironment and can also support drug delivery, therefore could be an ideal form of cell therapy (1). The success of cell therapy depends on the most efficient delivery to the site of disease and yet physical factors that regulate cell trafficking in the liver are still poorly understood, in this project we aim to focus on liver endothelial cells that are the gatekeepers for cell migration from the circulation into diseased liver tissue. We will study both how fluid flow/shear stress exposure and the underlying stiffness of the endothelial barrier impacts on monocyte capture and migration. Using a flow based assay we can perfuse monocytes over human endothelial monolayers and accurately control the flow to reflect the shear stress in the liver/tumour microenvironment (2). Incorporating different matrix coatings reflecting composition seen in liver disease will also alter endothelial stiffness properties. Additionally, we will assess how the pre-activation of monocytes to macrophages and pre-loading with cargo can impact on their migratory pathways.