A new method making cancer cells more visible to the immune system could improve how well immunotherapy works against a range of different tumours, potentially leading to more effective treatment for patients, according to a new study led by a team of UCL researchers.
The study, published in Immunity, focuses on a cellular process called Nonsense-Mediated mRNA Decay (NMD), which acts as a quality-control system inside cells. Its job is to detect and destroy genetic messages - known as RNA - that are faulty and could otherwise produce broken or potentially harmful proteins that can damage cells or contribute to disease.
While NMD is important for keeping healthy cells functioning properly, researchers have found that it may also be helping cancer cells hide from the immune system.
Immunotherapies work by helping the body's immune system recognise and attack tumours. These treatments rely on small molecular "flags" called antigens, which appear on the surface of cancer cells to signal when something is wrong. However, many tumours do not display enough of these flags for the immune system to detect them effectively, allowing them to grow undisturbed.
The research team, led by Dr Roberto Vendramin (UCL Cancer Institute), discovered that by blocking the NMD process, faulty RNA on the tumour didn't get cleaned up. Instead of being destroyed, this faulty RNA was used by the cell to make abnormal proteins. These proteins were then broken down into small fragments, which were displayed on the surface of cancer cells as antigens. This allowed a large number of previously hidden antigens to be recognised by the immune system, improving the body's response to immunotherapy.
Before blocking NMD, cancer cells do produce faulty RNA, but it is quickly destroyed, meaning little to no abnormal proteins are made. Only a very small number of antigens appear on the cell surface – too few to be noticed by the immune system. After blocking NMD, the faulty RNA remains and makes abnormal proteins that break down and are displayed on the cell surface as antigens.
Dr Vendramin said: "Immunotherapy has already transformed cancer care, but too many patients still don't benefit because their tumours remain effectively invisible to the immune system. By preventing the destruction of faulty RNA, we allow them to produce abnormal proteins which eventually become antigens and make cancer cells easier to see. Increasing the visibility of antigens on cancer cells may help the immune system target cancers with few genetic mutations.
"Once successfully developed into a treatment, our approach could benefit a wide range of cancer patients, particularly those whose tumours do not currently respond well to immunotherapy. It has the potential to improve immunotherapy response rates, which could translate into improved long-term survival and better outcomes for patients."
Because the strategy targets a common feature of cancer cells - their tendency to produce faulty RNA - it has the potential to work across many different tumour types, rather than being limited to specific cancers. This could make it particularly useful for patients whose tumours have a low number of DNA mutations. These make up the majority of cancers and are often less responsive to current immunotherapies.
Researchers say it could be especially relevant for patients whose tumours already contain immune cells but are not effectively controlled by them, including some colorectal, breast and kidney cancers. It may also be used alongside existing immunotherapies to enhance their effectiveness, even in cancers where these treatments already show some success.
Although the research is still at an early stage, there is growing interest in developing drugs that can target the NMD pathway. Scientists think that potential drug candidates could emerge within the next few years, with early-stage clinical trials possible within about five years.
