Researchers at the Francis Crick Institute and Barts Cancer Institute, Queen Mary University of London, have found that the presence of a protein known as CD74 could help determine which bowel cancer patients are likely to benefit from immunotherapy.
Researchers at the Francis Crick Institute and Barts Cancer Institute, Queen Mary University of London, have found that the presence of a protein known as CD74 could help determine which bowel cancer patients are likely to benefit from immunotherapy.
If implemented in clinical settings, testing for this protein may allow hundreds of patients, who previously wouldn’t have qualified, to access this type of treatment.
Bowel cancer ranks as the fourth most prevalent cancer in the UK and is the second leading cause of cancer-related death. There are two main types of this disease: one where DNA repair proteins are missing or not functioning (the deficient subtype), and another where these proteins are present (the proficient subtype).
Immunotherapy drugs, which enhance the immune system’s ability to combat tumors, have significantly changed the treatment landscape for the deficient subtype of colorectal cancer.
Despite their effectiveness, these drugs work for only about half of those affected, while individuals with the proficient subtype, who constitute roughly 90% of all cases, are currently excluded from receiving immunotherapy.
A study published today in Cancer Cell examined the reasons behind the varied responses to immunotherapy in bowel cancer patients and explored how to expand the pool of those who could benefit. The research found that the levels of a protein called CD74 could indicate whether patients will respond to immunotherapy, regardless of their cancer subtype.
The significance of the immune environment
The researchers first analyzed the immune cells surrounding various tumors since the presence of these cells can significantly influence a patient’s response to immunotherapy. They reviewed samples from both subtypes, comparing those who responded to the treatment with those who didn’t.
The study revealed that three specific immune cell types are necessary for a tumor to respond to treatment: T cells, NK cells (natural killer cells), and macrophages, which signal threats to the body.
When all three immune cell types were present near cancer cells, the T cells generated molecules known as interferons, which in turn triggered signals in the macrophages and tumor cells.
This signaling was notably stronger in the tumours of the deficient subtype that responded to immunotherapy; however, some patients with the proficient subtype exhibited similar signaling levels, indicating that their immune systems might also be primed to benefit from immunotherapy.
CD74: an indicator for immunotherapy success
The next step for the researchers was to find an efficient way to assess whether the immune system was suitably conditioned for immunotherapy to be effective.
Using an advanced technique called spatial transcriptomics, they discovered that T cells prompted nearby macrophages and tumor cells to produce CD74, and tumors responding to immunotherapy had elevated CD74 levels.
To evaluate the potential of CD74 as a predictive clinical marker for immunotherapy response, the team analyzed samples from several international clinical trials involving proficient subtype patients.
The findings indicated that those who reacted positively to immunotherapy had significantly higher levels of CD74 than non-responders.
This suggests that measuring CD74 levels could predict immunotherapy responsiveness in bowel cancer patients, regardless of subtype.
Importantly, this implies that some individuals with the proficient subtype, presently deemed ineligible for immunotherapy, may still benefit from it.
Francesca Ciccarelli, Principal Group Leader of the Cancer Systems Biology Laboratory at the Crick and Professor of Cancer Genomics at Barts Cancer Institute, remarked: “Immunotherapy drugs can be incredibly effective for some bowel cancer patients, yet most are not able to receive these treatments, and we currently lack a way to predict responses reliably.
“Our research indicates that evaluating CD74 levels — which suggest that the immune system is ‘in an optimal state’ for combating the tumor — may broaden access to immunotherapy. This could transform treatment for many individuals with the proficient bowel cancer subtype, translating to a substantial number of patients across the UK. Moreover, it might help identify those with the deficient subtype who are unlikely to respond, preventing unnecessary side effects.”
Kalum Clayton, a former postdoctoral researcher at the Crick and co-first author alongside Pietro Andrei and Amelia Acha, added: “Our study illustrates how cutting-edge technology combined with computational analysis can tackle significant clinical challenges. For an early-career researcher, witnessing how our findings can positively impact patients and their families is highly gratifying.”
The research team is currently collaborating with Cancer Research Horizons to translate these findings into a practical clinical test. They also plan to investigate why macrophages and tumor cells overproduce CD74 and whether this marker is found in other cancer types.
Anna Kinsella, Science Engagement Manager at Cancer Research UK, commented: “Immunotherapy treatments, including immune checkpoint inhibitors, harness the immune system’s power to combat cancer. While beneficial for some bowel cancer patients, these treatments do not work for everyone.
“Although additional research is required, studies like this that delve into tumor biology help researchers identify ways to predict when immunotherapy will be effective. In the future, this could enable clinicians to personalize treatment plans, providing wider access to immunotherapy for bowel cancer patients.
“Understanding cancer biology is essential for discovering improved methods for prevention, detection, and treatment, allowing individuals to lead longer, healthier lives without the fear of cancer. This is why discovery research remains central to our work at Cancer Research UK.”
The team also partnered with UCL, the University of Pisa, King’s College London, the Sarah Cannon Research Institute, and the Veneto Institute of Oncology.
