Scientists from University College London (UCL), with support from Oxford University, the Royal Free London Foundation and Leiden University of Medicine in the Netherlands, have identified a new type of immunotherapy to fight hepatitis B (HBV).
Chronic HBV causes 880,000 deaths worldwide annually from cirrhosis and liver cancer (hepatocellular carcinoma, HCC). The liver is an immunologically tolerant organ: the immune system does not respond to a foreign antigen, since it perceives it as its own. This limits hypersensitivity to foodborne antigens and bacteria from the intestine through the portal vein. A special interaction between the tolerogenic microenvironment of the liver (hepatocytes, lymphocytes and non-perchemal cells) suppresses the adaptive immune response of T cells responsible for fighting viruses and tumors. In the absence of this reaction, the virus can stay in the cells of the organ for a long time and destroy it: hepatitis B affects the liver, inserts the virus DNA into hepatocytes and, if untreated, can lead to fibrosis or a tumor of the organ.
For the study, the scientists used immune cells removed from the patient’s liver and tumor tissues in vitro. They found that in response to blockage of the enzyme acyl-CoA cholesterol acyltransferase (ACAT) by ACAT inhibitors, the activity of specific immune cells is increased: they can fight virus-associated cancers and inhibit the replication of hepatitis B. Oral ACAT inhibitors such as avazimib are well tolerated in humans as drugs to lower cholesterol levels.
“Chronic hepatitis B infection is a serious global health problem and the most common cause of liver cancer in the world. Developing new therapeutic options is critical to improving patient care. Immune cells, such as T cells, are necessary to fight viruses and tumors, but are often dysfunctional and unable to control disease. In most cases, current treatment standards are unable to eliminate the virus, prevent the development of cancer, or save immune cells. In this study, we aimed to directly inhibit the virus and stimulate the immune cells that fight it, ”said lead author Professor Mala Maini.
An experiment at UCL has shown that ACAT inhibitors enhance human antiviral T cells to kill the virus. This immune response is different from the treatments currently available. The immunostimulatory effect was particularly pronounced in T cells found in HBV-infected liver as well as in tumor tissues. ACAT inhibitors give T cells the ability to overcome the peculiarities of local immunity and allow them to target both the virus and malignant tumors. Other antiviral drugs have not shown the same effect.
“The modulation of cholesterol metabolism by ACAT inhibitors has unique effects on virus and tumor while at the same time stimulating T cells to fight them. This allows us to fight the disease in several directions at the same time. It is already known that the cholesterol-modifying drug is safe for humans, and we hope that our research will serve as the basis for the development of clinical trials combining cholesterol modulation with other therapies. Our results open up exciting new opportunities for treating patients with chronic viral infections and cancer, ”says co-author Dr. Natalie Schmidt.
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