Just as the universe began with a colossal explosion, bowel cancer also experiences a “Big Bang” moment that determines how it will grow and spread, according to new research supported by Cancer Research UK and the Wellcome Trust.
Scientists from The Institute of Cancer Research in London, the Fondazione Human Technopole in Milan, and Chalmers University of Technology in Sweden discovered that this pivotal event occurs when cancer cells first manage to hide from the immune system. This process, called immune escape, allows the cells to evade detection and continue developing unchecked.
During immune escape, bowel cancer cells disrupt the genes that normally allow the body’s immune defenses to recognize them as a threat. Once this happens, the researchers found that the cancer’s ability to disguise itself remains largely unchanged as it grows.
The findings could help doctors identify patients more likely to respond to immunotherapy, including experimental bowel cancer vaccines that train the immune system to target and destroy cancer cells.
How Bowel Cancer Outsmarts the Immune System
Professor Trevor Graham, Professor of Genomics and Evolution and Director of the Centre for Evolution and Cancer at The Institute of Cancer Research, explained the significance of the discovery:
“Some bowel cancers are ‘born to be bad.’ How they interact with the immune system is set early on.
“Immunotherapy and bowel cancer vaccines hold enormous promise for treating the disease. Our research suggests that a bowel cancer’s relationship with the immune system doesn’t change very much as it grows. If we can target that relationship early on, treatment should have a stronger chance of success.
“As bowel cancer treatment becomes increasingly personalized, understanding how tumors evolve and change matters even more than it did before. Like the explosion which set the course of the universe, bowel cancer’s Big Bang gives us the biggest clues of what its future holds and how we might change that future.”
A Common and Challenging Cancer
Bowel cancer is the fourth most common cancer in the UK, with about 44,100 new cases each year — around 120 every day. Approximately 15% of these cases respond well to immunotherapy, while the majority remain resistant to this treatment approach.
Currently, several types of bowel cancer vaccines are being tested in clinical trials. These are designed to help the immune system recognize and destroy returning or newly forming cancer cells after surgery or other treatments.
Study lead author Eszter Lakatos, a mathematical biologist at Chalmers University of Technology and the University of Gothenburg, Sweden, said:
“Our research group has investigated and found answers to how cancer cells render themselves invisible to the immune system. Our hope is that these insights will eventually lead to more targeted, effective and early treatments, in addition to surgery.”
To uncover these mechanisms, the research team analyzed tumor and immune cells from 29 people with bowel cancer. They sequenced the DNA and RNA from each sample and examined how tightly the DNA was wound around proteins in the chromosomes (a process known as epigenetics).
The scientists found that epigenetic changes in cancer cells alter how DNA is “read” to produce RNA, which carries the instructions for making proteins. These changes can reduce the number of neoantigens — “red flag” proteins that alert immune cells to danger — on the surface of cancer cells. With fewer neoantigens, the immune system struggles to recognize and destroy the tumor.
Toward More Effective Immunotherapy
The researchers believe that combining immunotherapy with drugs that modify the epigenome could improve treatment outcomes. Such a combination might increase the number of neoantigens displayed by cancer cells, making them easier for the immune system to target. Further testing will be needed before this approach can move into clinical trials.
Dr. Catherine Elliott, Director of Research at Cancer Research UK, said:
“To beat bowel cancer for everyone, we need to understand what happens at the very earliest stages of the disease. No matter how different bowel cancer tumors can look, one defining moment at the start makes a big difference to how the cancer grows.
“Bowel cancer has an insidious ability to resist treatment. Immunotherapy is starting to work well for patients, but it doesn’t work for everyone. This research helps us understand why, as well as giving us new insights to make immunotherapy work better for bowel cancer.”
Understanding the Disease’s Earliest Moments
Tom Collins, Research Lead for Discovery Research at the Wellcome Trust, added:
“Through tracing the earliest stages of bowel cancer, the research team has shed valuable new light on a mechanism that could lead to more targeted, effective and early treatments.
“This is a powerful example of discovery science. Research at this molecular level has provided a deeper understanding of how bowel cancer develops, which could lead to the improved health outcomes for patients in the long-term.”
The study, titled “Epigenetically driven and early immune evasion in colorectal cancer evolution,” was published on November 5 in Nature Genetics.
