Researchers at University College London (UCL) have discovered a new immunotherapy to fight against the hepatitis B virus (HBV), which is the most common cause of liver cancer.
Every year, chronic hepatitis B causes around 880,000 deaths from liver cirrhosis and hepatocellular carcinoma/liver cancer (HCC).
The novel study used immune cells isolated directly from patients’ liver and tumour tissue in order to demonstrate that targeting acyl-CoA:cholesterol acyltransferase (ACAT), an enzyme that aids the management of cholesterol levels in the cells, was ‘highly effective’ at boosting immune responses.
The findings, published in Nature Communications, indicate that blocking the ACAT with ACAT inhibitors enhances the specific immune cells that can fight against both the virus and related cancerous tumours, exhibiting its efficiency as an immunotherapy.
The team found that inhibiting ACAT also obstructed HBV’s own replication, thus also working as a direct antiviral. When taken orally, ACAT inhibitors, like avasimibe, have formerly demonstrated good potential as cholesterol-lowering drugs in humans.
Lead author, professor Mala Maini, of the UCL Division of Infection and Immunity, commented: “Chronic hepatitis B virus infection is a major global health problem and the most common cause of liver cancer in the world.
“The development of novel therapeutic options is crucial to improve patient care. Immune cells such as T cells are indispensable for fighting viruses and tumours but are often highly dysfunctional and fail to control these diseases. Current standard of care treatments are often incapable of eliminating the virus, do not prevent cancer development and do not rescue immune cells.
“In this study we aimed to identify a treatment target to directly inhibit the virus while also boosting the immune cells fighting it.”
Cholesterol is a fat that we consume every day in our diets and can exercise many functions within various cells of the body. HBV infects the liver, which is highly enriched in cholesterol and is known for restricting local immune responses.
During the study, the team used human liver disease tissue samples in vitro, and demonstrated that ACAT inhibitors enhanced human antiviral T cells proficient at eliminating the virus. This response differentiates with currently available therapies.
The immune-boosting effect was particularly remarkable in T cells located in the HBV-infected liver and within liver cancer, surmounting the local restraints on immune cell function, permitting the T cells to target both the virus and cancerous cells.
The group then worked alongside Professor Jane McKeating’s lab at the University of Oxford to highlight that ACAT inhibitors may possibly block the HBV life cycle in a manner that other antivirals cannot. Therefore, these drugs have a distinctive combination of antiviral and immunotherapeutic effects.
First author, Dr Nathalie Schmidt, also of the UCL Division of Infection and Immunity, explained: “We have found a highly effective novel target for the treatment of chronic hepatitis B virus infection and liver cancer.
“Modulating cholesterol metabolism with ACAT inhibitors has the unique features of directly targeting the virus and tumours while at the same time boosting the T cells that fight them. This enables us to tackle the disease from multiple directions at the same time.”
Dr Schmidt added: “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.”