Do you know: Protein level predicts response to immunotherapy in bowel cancer
in 2025
Researchers at the Francis Crick Institute and Barts Cancer Institute, Queen Mary University of London, have shown that the amount of a protein called CD74 can indicate which people with bowel cancer respond best to immunotherapy.
If integrated into the clinic, testing for this protein could allow hundreds of patients who were previously ineligible to benefit from this type of treatment.
Bowel cancer is the fourth most common cancer in the UK, and the second most common cause of cancer death. The disease falls into two types: one in which proteins that repair DNA errors are missing or deficient (the deficient subtype), and one in which this machinery is intact (the proficient subtype).
Cancer immunotherapy drugs, which boost the immune system to fight the tumor, have revolutionized the treatment of the deficient subtype of colorectal cancer.
However, these drugs only work in about half of these individuals, and people with the fluent subtype, who account for ~90% of all cases, are not currently eligible for immunotherapy treatment.
In a study published today in Cell Cancerthe researchers investigated why immunotherapy only works for some people with bowel cancer, and how we could increase the number of patients who could benefit from this treatment. They found that expression levels of a protein called CD74 can predict response to immunotherapy, independent of subtype.
The importance of the immune environment
The team first studied the immune cells associated with different tumors, as the presence or absence of these cells can play a large role in a person’s response to immunotherapy. They examined samples from both subtypes, and from people who responded to immunotherapy drugs versus people who did not.
They discovered that three types of immune cells needed to be present for the tumor to respond to treatment: fighter cells called T and NK cells, and cells called macrophages, which put flags on their surfaces to draw attention to a threat to the body.
When all three immune cell populations were present and near cancer cells, the T cells produced molecules called interferons, which triggered a signal in macrophages and tumor cells.
This signal was much higher in tumors of the deficient subtype that responded to immunotherapy, but, surprisingly, some patients in the proficient subtype also produced a comparable signal, suggesting that their immune system may be in the right state to benefit be removed from immunotherapy.
CD74: a marker for immunotherapy response
Next the team looked for a simple way to check if the immune system was in the right condition for immunotherapy to be successful.
Using a pioneering technique called spatiotemporal transcription, they observed that T cells stimulated macrophages and nearby tumor cells to produce a protein called CD74 and that tumors responding to immunotherapy drugs produced higher levels height of CD74.
To test whether CD74 might hold promise as a clinical marker to predict which patients would benefit from immunotherapy, the researchers studied samples from several international clinical trials that tested immunotherapy in groups of people with the fluent subtype.
They found that people who responded to immunotherapy had significantly higher levels of CD74 than those who did not.
The results suggest that measuring CD74 levels could predict whether someone with bowel cancer will respond to immunotherapy, independent of their type.
Crucially, this means that some people with the fluent subtype, who are not currently eligible for immunotherapy, may benefit from this treatment.
Francesca Ciccarelli, Principal Group Leader of the Cancer Systems Biology Laboratory at Crick, and Professor of Cancer Genomics at Queen Mary University of London’s Barts Cancer Institute, said: “Immunotherapy drugs can be very successful for people with bowel cancer, but now they have more. These drugs cannot be prescribed to patients and, even when patients are eligible, we do not know in advance who will respond to them.
“Our work suggests that testing for CD74 levels — which indicates that the immune system is ‘well enough’ to fight the tumor — could expand access to immunotherapy. a revolution for a large proportion of people with this subtype of bowel cancer, which represents a large number of patients across the UK in real terms.
Kalum Clayton, former postdoc at the Crick and joint first author with Pietro Andrei and Amelia Acha, said: “Our work shows how state-of-the-art technologies combined with computational analysis can address important clinical questions. As an early career research scientist, it is very rewarding to see our work benefiting patients and their families.”
The research team is now working with Cancer Research Horizons to develop the results into a test that can work in the clinic. They will also research why macrophages and tumor cells overexpress CD74, and whether this marker is present in other types of cancer.
Anna Kinsella, Science Engagement Manager at Cancer Research UK, said: “Immunotherapy treatments, such as immune checkpoint inhibitors, use the power of the immune system to fight cancer. Although these treatments benefit some people with bowel cancer, they are not effective for everyone.
“Although more research is needed, studies like this — diving deep into tumor biology — help researchers find ways to predict when immunotherapy is likely to work. In the future, this could help clinicians tailor treatment and allow more people with bowel cancer to benefit from immunotherapy.
“Understanding the biology of cancer is vital to unlocking better ways to prevent, detect and treat it, so people can live longer and better lives free from the fear of cancer. That’s why Cancer Research UK, discovery research is at the heart of everything we do.”
The team also worked with UCL, the University of Pisa, King’s College London, the Sarah Cannon Research Institute and the Veneto Institute of Oncology.