Aggressive and highly-mutated cancers are engaged in an “evolutionary arms race” with the immune system, new research suggests.
Gullet and stomach cancers with faults in their systems for repairing DNA build up huge numbers of genetic mutations which make them resistant to treatments like chemotherapy.
But these numerous mutations mean they appear foreign to the immune system, leaving them vulnerable to attack, and susceptible to new immunotherapies.
Scientists at the Institute of Cancer Research, London (ICR), found that these “hyper-mutant” tumours rapidly evolve strategies to disguise themselves from the immune system and evade attack.
They hope that in the future, the findings could help optimise treatment with immunotherapy, and other drugs such as chemotherapy.
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The study, published in Nature Communications, was funded by Cancer Research UK and the Schottlander Research Charitable Trust.
Dr Marco Gerlinger, team Leader in translational oncogenomics at the ICR, said: “Our new study has shown that in highly mutated tumours, cancer and the immune system are engaged in an evolutionary arms race in which they continually find new ways to outflank one another.
“Watching hyper-mutated tumours and immune cells co-evolve in such detail has shown that the immune system can keep up with changes in cancer, where current cancer therapies can become resistant – and that we could use immunotherapies to shift the balance of this arms race, extending patients’ lives.
“Next, we plan to study the evolutionary link between hyper-mutant tumours and the immune system as part of a new clinical trial looking at the possible benefit of immunotherapy in bowel cancer.”
Finding the faults in hyper-mutant stomach tumours
In the new study, researchers analysed the genetic landscape of four tumours from the stomach and gullet which had a fault in one or more important DNA repair genes.
They analysed the genetic make-up of seven different areas from each patient’s tumour, and in sites to which their cancer had spread.
According to the research, the hyper-mutant stomach tumours had strikingly high levels of genetic variation, with an average of nearly 2,000 different gene faults.
This is much higher than the 436 faults found in skin cancer, the next most highly mutated cancer type analysed in the study.
Extreme heterogeneity, large trunks and parallel evolution in MSI gastric cancer. Our study in @NatureComms https://t.co/INefeLtlno Together with high immunotherapy sensitivity, suggests that mutational heterogeneity does not deterr immune recognition when trunks are large pic.twitter.com/Bz54JJm6N4
— Marco Gerlinger (@MarcoGerlinger) January 16, 2020
Different areas of the same tumour showed extreme variation in their mutations, enabling rapid Darwinian evolution.
Researchers found the two stomach and gullet tumours with the highest level of infiltration from immune cells had each developed several mutations that allowed them to evade immune attack.
These mutations occurred in genes which normally help immune cells to recognise and attack cancer cells.
When the genes fail to function as normal, the immune system is unable to spot cancer cells despite their large numbers of mutations.
Professor Paul Workman, chief executive of the ICR, said: “Cancer evolution is the biggest challenge in cancer research and treatment today – and deepening our understanding of how tumours evolve in response to treatment is absolutely key to finding ways of overcoming drug resistance.
“This fascinating new study shows how cancers can co-evolve with the immune system, with each responding to changes in the other.
“Without treatment, cancers will be destined to win this evolutionary arms race, but we can tip the balance in favour of the immune system through carefully designed use of immunotherapy.”
How does radiation kill cancer if it causes cancer?
Asked by: Odysseus Ray Lopez, US
It’s rather like the way guns can be used to commit crime, or stop it. Radiation causes cancer because its high-energy photons can cause breaks in the DNA strands in your cells. Cells can repair this damage up to a point, but sometimes the repair isn’t perfect and leaves some genes defective. If the break affects one of the many tumour-suppressing genes in your DNA, that cell can become cancerous. But cancer cells are also more vulnerable to radiation than ordinary cells. Part of what makes them cancer cells is their ability to divide rapidly and this normally means that some of the DNA ‘spellcheck’ mechanisms are turned off.
So when a cancer cell suffers a break in a DNA strand, it’s less likely to repair it correctly. Depending where the break occurs, it might either kill the cell outright, or make it reproduce more slowly. Radiation therapy uses a focused beam that is aimed at just the part of the body with the tumour, and the dose is carefully calculated to cause the minimum collateral damage to healthy cells. Even so, radiation therapy does very slightly increase your chances of developing a second cancer.