International research involving the University of Adelaide has helped to better understand how a diseased liver promotes the development of cancer. This work could lead to improvements in treating liver cancer, which is the second leading cause of cancer deaths worldwide.
For the first time, researchers have discovered that chronic inflammation of the liver suppresses the natural immune defence systems against cancer. This immune suppression enables the growth and potential spread of cancer.
In a further breakthrough, the research team has successfully used drugs and genetic engineering to switch off the inflammation-associated immune suppression, showing that the growth of cancer can be reversed or prevented.
The results of this groundbreaking work – led by the University of California San Diego, and involving an international team of researchers including the University of Adelaide – are published today in Nature.
“Chronic inflammation drives many cancers, and liver cancer especially, but until now we haven’t completely understood the mechanisms by which this has been happening,” says co-author and leading international liver disease expert Professor Alastair Burt, Executive Dean of the Faculty of Health and Medical Sciences, University of Adelaide.
“For many years we’ve thought that inflammation directly affects liver cancer cells, stimulating their division and protecting them from cell death, helping them to grow and spread. However, we’ve now found that inflammation in a diseased liver actively prevents what we call ‘immunosurveillance’, the adaptive immune response which is part of the body’s frontline defence system against cancer.
“Because of this discovery, we’re now having to re-evaluate the importance of adaptive immunity in preventing the formation and spread of tumours,” Professor Burt says.
Liver cancer is caused by chronic liver inflammation from hepatitis B or C, excess alcohol consumption, and diseases such as non-alcoholic steatohepatitis (NASH). Currently, the mainstay of treatment is surgical removal or ablation (the destruction of tumours).
In studies involving both mice and humans, the researchers found that chronic liver inflammation triggered the accumulation of a specific class of immunosuppressive cells. This prevented the normal immune system from recognising and attacking newly emerging liver cancer cells.
“In effect, what happens is the liver’s immune system starts to fight itself. The winner of this fight is the cancer, which continues to grow and spread, unhindered by the normal anti-tumour response,” Professor Burt says.
“This wouldn’t occur if it were not for the chronic inflammation of the liver,” he says.
In the case of these studies, the team looked at non-alcoholic steatohepatitis (NASH), a metabolic disorder that causes liver damage, inflammation, fibrosis and numerous cell mutations. NASH itself is associated with obesity and type 2 diabetes, and is expected to become the leading cause of liver cancer in the western world.
But there is more exciting news, Professor Burt says.
“We’ve been able to switch off the active mechanism that interferes with the normal immune response. This has been done through the use of drugs, or by genetic engineering in mice, targeting a molecule known as PD-L1.
“When PD-L1 is inhibited, the normal adaptive immunity is no longer affected and can resume its job, suppressing and clearing tumours from the liver.”
The group’s research helps to explain why a class of drugs known as anti-PD-1 drugs, which block the receptor for PD-L1, may be effective at combating liver cancer.
“We can expect to see more about this class of drugs in the near future, as they have recently been approved for the treatment of advanced liver cancer,” Professor Burt says.
This research is led by University of California San Diego’s School of Medicine and involves researchers from Jinan University in China, Newcastle University in the UK, University of Adelaide in Australia, the Repertoire Genesis Incorporation in Japan, and the Salk Institute for Biological Studies in the US.