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Researchers at UCL have identified a new immunotherapy to fight the hepatitis B virus (HBV), the most frequent cause of liver cancer in the world.
The pioneering study used immune cells isolated directly from patient liver and tumour tissue, to demonstrate that targeting acyl-CoA:cholesterol acyltransferase (ACAT), an enzyme which helps to manage cholesterol levels in cells, was highly effective at boosting immune responses.
Released in Nature Communications, the findings show that blocking the action of ACAT with ACAT inhibitors boosts the specific immune cells that can fight both the virus and associated cancerous tumours, demonstrating its effectiveness as an immunotherapy. Inhibiting ACAT was also found to impede HBV’s own replication, thereby also acting as a direct antiviral. ACAT inhibitors like avasimibe, taken orally, have previously been shown to be well-tolerated as cholesterol-lowering medication in humans.
Explaining the study, lead author Professor Mala Maini (UCL Division of Infection & Immunity), stated:”Chronic hepatitis B virus infection is a major global health problem and the most frequent cause of liver cancer in the world.
“The development of novel therapeutic options is crucial to enhance patient care. Immune cells such as T cells are crucial for fighting viruses and tumours but are often highly dysfunctional and don’t control these diseases. Current standard of care treatments are often incapable of eliminating the virus, do not prevent cancer development and don’t rescue immune cells.
Cholesterol is a lipid (fat) that we ingest daily in our diets and that can exert multiple roles within different cells of the body.
In this study, using human liver disease tissue samples in vitro, Professor Maini’s lab at UCL showed that ACAT inhibitors boosted human antiviral T cells capable of eliminating the virus. This response is in contrast to currently available therapies. The immune-boosting effect was especially striking in T cells found in the HBV-infected liver and within liver cancer, overcoming the local restraints on immune cell function, allowing the T cells to target both the virus and cancerous cells.
The Maini group then collaborated with Professor Jane McKeating’s laboratory at the University of Oxford to demonstrate that ACAT inhibitors could also block the HBV life cycle in a manner that other antivirals are unable to. These drugs therefore have a unique combination of antiviral and immunotherapeutic effects.
Commenting on the findings, first author Dr Nathalie Schmidt (UCL Division of Infection & Immunity), stated:”We’ve found an extremely effective novel target for the treatment of chronic hepatitis B virus infection and liver cancer.
“Modulating cholesterol metabolism using ACAT inhibitors has the distinctive features of directly targeting the virus and tumours while at the same time fostering the T cells which fight them. This enables us to tackle the disease from several directions at exactly the same time.”
The cholesterol-modifying drug is already known to be safe in humans and we hope that our study now informs the development of clinical trials combining cholesterol modulation with other immunotherapies. In summary, our findings offer exciting new possibilities for the treatment of patients with chronic viral infections and cancer.”
Dr Nathalie Schmidt, UCL Division of Infection & Immunity
University College London
Schmidt, N.M., et al. (2021) Targeting human Acyl-CoA:cholesterol acyltransferase as a dual viral and T cell metabolic checkpoint. Nature Communications. doi.org/10.1038/s41467-021-22967-7.
