Derek Mann

• WP 1 Co-Lead, and Professor of Hepatology

Immunotherapy is now a first-line treatment for liver cancer, however it is not always successful and many patients are resistant. In our latest research paper we asked if manipulation of specialised immune cells known as ‘neutrophils’ can improve immunotherapy and especially in the context of fatty liver disease which is a major cause of liver cancer. To manipulate neutrophils, we used a highly selective inhibitor (AZD5069) of a receptor called CXCR2 which is found on the surface of the neutrophil. When AZD5069 and the immunotherapeutic agent anti-PD-1 were used to treat mice bearing liver tumours on the background of a fatty liver they combined to deliver an improved therapeutic response when compared to mice treated with anti-PD1 alone, with a reduced tumour burden and prolonged survival. Mechanistic investigations suggested that the tumour-associated neutrophils in treated mice had reprogrammed into a state where they can stimulate the recruitment and activity of other immune cells (cytotoxic T cells and dendtitic cells) that are known to be essential for immunotherapy to succeed. The paper has established the concept that neutrophils can be pharmacologically manipulated to promote anti- tumour immunity and this idea will be tested in a clinical trial (CUBIC) which will ask if AZD5069 can enhance immunotherapy in patients with advanced HCC.

You can view Derek's University webpage here, and the website for his research group here.