By Lina carolina 
Researchers at the Francis Crick Institute and the Barts Cancer Institute, Queen Mary University of London, have identified a critical protein marker, CD74, that could significantly broaden the eligibility of bowel cancer patients for life-saving immunotherapy treatments. This groundbreaking discovery, published in the esteemed journal Cancer Cell, suggests that measuring CD74 levels in tumours could predict a patient’s response to immunotherapy, regardless of their cancer’s specific molecular subtype. If integrated into clinical practice, this simple test has the potential to offer hundreds of patients, previously deemed ineligible, access to one of modern medicine’s most powerful anti-cancer weapons.
Bowel cancer, a formidable adversary, stands as the fourth most prevalent cancer in the United Kingdom and tragically, the second leading cause of cancer-related mortality. The disease’s complexity is underscored by its classification into two primary subtypes: the deficient subtype, characterized by missing or impaired DNA repair proteins, and the proficient subtype, where this error-correction machinery remains intact. For years, immunotherapy, a revolutionary approach that harnesses the patient’s own immune system to combat cancer, has transformed the treatment landscape for the deficient subtype of colorectal cancer. These therapies, which essentially "unleash" the immune system against malignant cells, have demonstrated remarkable efficacy in a subset of these patients. However, the stark reality is that these treatments are only effective in approximately half of eligible individuals. More critically, the proficient subtype, which accounts for a staggering 90% of all bowel cancer cases, has historically been excluded from the benefits of immunotherapy due to a lack of predictive biomarkers.
The research team embarked on a comprehensive investigation to unravel the enigma behind immunotherapy’s variable success and to devise strategies for extending its reach. Their meticulous analysis pinpointed the expression levels of the protein CD74 as a key determinant of immunotherapy response, operating independently of the tumour’s subtype. This finding represents a paradigm shift in how bowel cancer treatment might be approached, moving beyond rigid subtype classifications to a more nuanced understanding of the immune microenvironment’s readiness to engage in a fight against cancer.
Unraveling the Immune Microenvironment’s Role in Treatment Response
The cornerstone of this research involved a deep dive into the intricate interplay between immune cells and cancerous growths. Scientists understand that the presence and activity of immune cells surrounding a tumour can profoundly influence a patient’s response to immunotherapy. The study meticulously examined tumour samples from both deficient and proficient subtypes, comparing those who responded favourably to immunotherapy drugs with those who did not.
A crucial observation emerged: the successful recruitment and presence of three distinct types of immune cells were essential for a tumour to respond to treatment. These included cytotoxic T cells and Natural Killer (NK) cells, often referred to as the "fighter cells" of the immune system, along with macrophages. Macrophages play a vital role in initiating an immune response by presenting molecular "flags" on their surfaces, effectively signalling the presence of a threat to other immune components.
When all three of these immune cell populations were present and strategically positioned in close proximity to cancer cells, a potent cascade of molecular signals was initiated. T cells, stimulated by this environment, released molecules known as interferons. These interferons, in turn, triggered a significant signalling pathway within macrophages and the tumour cells themselves. This signalling was particularly pronounced in tumours of the deficient subtype that responded to immunotherapy. However, the researchers observed a surprising finding: a comparable level of this crucial signal was also detected in a subset of patients with the proficient subtype. This suggested that, contrary to previous assumptions, some individuals with the proficient subtype might possess an immune system primed and ready to benefit from immunotherapy.
CD74: A Promising Biomarker for Immunotherapy Efficacy
Having established the importance of the immune microenvironment, the next critical step for the research team was to identify a straightforward and reliable method for assessing whether this environment was optimally configured for immunotherapy to succeed. This led them to investigate the protein CD74.
Employing cutting-edge spatial transcriptomics technology, a sophisticated technique that allows for the analysis of gene expression within specific locations in a tissue sample, the scientists observed a compelling correlation. They found that T cells, when activated, stimulated nearby macrophages and tumour cells to produce CD74. Crucially, tumours that were demonstrably responding to immunotherapy drugs exhibited significantly higher levels of CD74 expression.
To rigorously validate CD74’s potential as a clinical biomarker, the researchers extended their investigation to encompass samples from several international clinical trials. These trials specifically focused on immunotherapy treatments administered to groups of patients with the proficient subtype of bowel cancer. The results were compelling: individuals who responded positively to immunotherapy consistently displayed markedly higher levels of CD74 compared to those who did not experience a therapeutic benefit.
Implications for Clinical Practice and Future Directions
The implications of these findings are profound. The ability to measure CD74 levels offers a tangible pathway to predict immunotherapy responsiveness in bowel cancer patients, irrespective of their subtype. This is particularly significant for the 90% of patients who fall into the proficient subtype, a vast majority who are currently excluded from this highly effective treatment modality. By identifying individuals within this group who possess the "right" immune environment, as indicated by elevated CD74, clinicians could potentially offer them a life-changing therapeutic option.
Francesca Ciccarelli, Principal Group Leader of the Cancer Systems Biology Laboratory at the Crick and Professor of Cancer Genomics at Queen Mary University of London’s Barts Cancer Institute, articulated the significance of this breakthrough. "Immunotherapy drugs can be hugely successful for people with bowel cancer," she stated, "but currently the majority of patients can’t be prescribed these drugs and, even when patients are eligible, we don’t know upfront who will respond." She further emphasized, "Our work suggests that testing for CD74 levels—which signal that the immune system is ‘just right’ to fight the tumour—could widen access to immunotherapy. This could revolutionise treatment for a sizeable fraction of people with the proficient bowel cancer subtype, which is a large number of patients across the UK in real terms. It could also be used to identify people with the deficient subtype who won’t respond, saving them from experiencing side effects unnecessarily." This dual benefit—expanding access for those who will respond and sparing unnecessary toxicity for those who won’t—underscores the clinical utility of this marker.
Kalum Clayton, a former postdoc at the Crick and joint first author of the study alongside Pietro Andrei and Amelia Acha, highlighted the power of interdisciplinary research. "Our work shows how state-of-the-art technologies coupled with computational analysis can address important clinical questions," he remarked. "As an early career research scientist, seeing the potential of our work to provide benefit to patients and their families is greatly rewarding." This sentiment underscores the direct impact of fundamental research on patient outcomes.
The research team is not resting on their laurels. They are actively collaborating with Cancer Research Horizons, an organization dedicated to translating scientific discoveries into tangible benefits for patients, to develop a robust clinical test based on these findings. Furthermore, their ongoing research aims to elucidate the precise mechanisms by which macrophages and tumour cells overexpress CD74 and to explore whether this promising marker is also present and predictive in other cancer types. This proactive approach signals a commitment to rapidly advancing this discovery from the laboratory bench to the patient’s bedside.
A Collaborative Effort and Broader Impact
The success of this research is a testament to extensive collaboration. Beyond the primary institutions, the study involved significant contributions from UCL, the University of Pisa, King’s College London, the Sarah Cannon Research Institute, and the Veneto Institute of Oncology. This multidisciplinary approach, drawing expertise from various centers of excellence, is crucial for tackling complex diseases like cancer.
Anna Kinsella, Science Engagement Manager at Cancer Research UK, underscored the importance of such discoveries within the broader landscape of cancer research. "Immunotherapy treatments, such as immune checkpoint inhibitors, use the power of the immune system to fight cancer," she explained. "Whilst these treatments benefit some people with bowel cancer, they aren’t effective for everyone." She further elaborated, "Although further research is needed, studies like this—diving deep into the biology of tumours—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." Cancer Research UK’s commitment to funding discovery research, as highlighted by Kinsella, is fundamental to unlocking innovative approaches that can improve and prolong lives.
The potential implications of this research extend beyond bowel cancer. If CD74 proves to be a reliable predictor of immunotherapy response across various cancer types, it could revolutionize the treatment of numerous malignancies. The current landscape of cancer immunotherapy, while offering hope, is often a process of trial and error. The identification of reliable biomarkers like CD74 is essential for moving towards a more personalized and precise approach to cancer care, ensuring that patients receive the most effective treatments with minimal unnecessary toxicity. The journey from scientific discovery to widespread clinical adoption is often a lengthy one, involving rigorous validation and regulatory approval. However, the findings presented by the Crick and Barts Cancer Institute researchers represent a significant leap forward, offering a tangible prospect of transforming immunotherapy from a treatment for a select few to a viable option for a much broader spectrum of bowel cancer patients.
