US scientists show how immune system 'prunes' tumours

In collaboration with the Press Association

Laboratory research by US scientists has shown for the first time how the body's immune system shapes how a tumour grows.

The finding, by a team at Washington University School of Medicine in St Louis, published in Nature, suggests that genetic information from within a patient's tumour could one day be used to rapidly create tailored vaccines to treat their disease.

It has long been known that the immune system can attack cancer, but that tumours eventually escape this assault. As a result, many labs worldwide are developing treatments that switch on the body's immune system and attack a tumour - so-called immunotherapy.

Key to this is to understand how the immune system interacts with a tumour as it grows. Over the years, evidence has emerged that tumour cells can recognise and 'prune' certain cells within a cancer, and that this can hold cancer in check for some time.

But tumour samples from patients and experimental models have already been exposed to - and survived - immune attack, making it difficult to pin down how the process unfolds.

The new research looked at how tumours grew in mice that had defective immune systems, and, in particular, at the faulty genes in their tumours.

Using 'next-generation' DNA sequencing, the researchers pinpointed mutations in the tumours growing in mice whose tumours hadn't been 'pruned'. They then used an online database to see whether any of these mutations could be used to trigger the immune system's alarm bells.

They found that one gene that was mutated in these animals' tumours - spectrin beta-2 - produced a faulty protein that was able to stimulate the immune system to attack tumours. The unmutated form of the gene was unable to do so.

The mutation was not present in tumours of mice who had a fully-functioning immune system, and further experiments showed how cells with this mutation had been 'edited out' by the immune system.

"We already have ways to identify specific targets for immunotherapy, but they are technically challenging, extremely labour-intensive and often take more than a year to complete," said senior author Professor Robert Schreiber.

"These difficulties have stood in the way of developing personalised immunotherapies for cancer patients, who often require immediate care for their disease. To our knowledge, this is one of the first studies to show that the faster methods provided by DNA sequencing can help. That opens up all kinds of exciting possibilities."

Professor Christian Ottensmeier, a Cancer Research UK immunotherapy expert from the University of Southampton, said the finding was "very exciting" but that there were hurdles to be cleared before patients could benefit.

"This research shows experimentally for the first time how the immune system can 'prune' the cells of a tumour as it develops. This is a process we've long suspected occurs, but the study shows us experimentally how this process works. The data suggest that, one day, we might be able to use the genetic information in patients' tumours to create better, more personalised immunotherapies," he said.

"But there are several hurdles to clear before we get there. For example, the researchers carried out this study by comparing mice with cancer who had no effective immune system, to mice in which the immune system is intact. We need to see how this 'pruning' works in people, and whether it can indeed yield information that can help patients. Nevertheless, this is a significant step forward in immunotherapy research and opens up many avenues for future work."

The team is now sequencing DNA in tumours from mice with normal immune systems to see if mutations that are not as readily discernible to the immune system can be identified.

Copyright Press Association 2012

References

  • Matsushita, H., Vesely, M., Koboldt, D., Rickert, C., Uppaluri, R., Magrini, V., Arthur, C., White, J., Chen, Y., Shea, L., Hundal, J., Wendl, M., Demeter, R., Wylie, T., Allison, J., Smyth, M., Old, L., Mardis, E., & Schreiber, R. (2012). Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting Nature DOI: 10.1038/nature10755