By Lina carolina 
Researchers at the Francis Crick Institute and Barts Cancer Institute, Queen Mary University of London, have identified a crucial 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 could become a standard diagnostic tool, potentially enabling hundreds of patients who were previously excluded from this therapy to benefit.
Bowel cancer, a formidable challenge to public health in the UK and globally, stands as the fourth most common cancer and the second leading cause of cancer-related mortality. Its complex nature is broadly categorized into two primary subtypes: the deficient subtype, characterized by missing or deficient DNA repair proteins, and the proficient subtype, where this DNA repair machinery remains intact. While immunotherapy, a revolutionary approach that harnesses the body’s own immune system to combat cancer, has transformed the treatment landscape for the deficient subtype, its efficacy remains limited to approximately half of these patients. Critically, individuals with the proficient subtype, representing a substantial 90% of all bowel cancer cases, have historically been ineligible for immunotherapy. This new research promises to dismantle that barrier.
Unraveling the Immune Microenvironment’s Role
The research team embarked on an in-depth investigation into the intricate factors dictating immunotherapy response in bowel cancer. Their primary focus was the immune cells residing within and surrounding tumours, as their presence and activity are pivotal in determining a patient’s susceptibility to immunotherapy. By meticulously examining samples from both deficient and proficient subtypes, and comparing individuals who responded positively to immunotherapy with those who did not, the scientists aimed to decipher the underlying mechanisms.
Their comprehensive analysis revealed a critical triumvirate of immune cells essential for a robust response to immunotherapy: cytotoxic T cells, often referred to as "fighter cells," Natural Killer (NK) cells, which also possess potent anti-tumour capabilities, and macrophages. Macrophages play a vital role in initiating an immune response by presenting "flags" – antigens – on their surfaces, thereby signaling the presence of a threat to the body’s defence system.
When these three immune cell populations were present in sufficient numbers and strategically positioned in close proximity to cancer cells, a crucial cascade of molecular signals was triggered. T cells released signaling molecules known as interferons, which in turn activated macrophages. This activation prompted macrophages to communicate with both tumour cells and other immune cells, amplifying the anti-cancer response. This signaling pathway was significantly more pronounced in tumours of the deficient subtype that demonstrated a positive response to immunotherapy. However, a surprising finding emerged: a subset of patients within the proficient subtype also exhibited a comparable level of this critical immune signaling. This observation strongly suggested that their immune systems might be primed and ready to benefit from immunotherapy, even without the characteristic DNA repair deficiency.
CD74: A Predictive Biomarker for Immunotherapy Success
The researchers then sought a straightforward and reliable method to assess whether the immune system was in the optimal state for immunotherapy to achieve success. Employing a cutting-edge technology known as spatial transcriptomics, which allows for the detailed analysis of gene expression within the spatial context of tissues, they observed a significant correlation between T cell activity, macrophage stimulation, and the production of the protein CD74. Their findings indicated that stimulated T cells were prompting nearby macrophages and tumour cells to produce CD74. Crucially, tumours that were responding effectively to immunotherapy drugs consistently displayed higher levels of CD74 expression.
To rigorously evaluate the potential of CD74 as a clinical biomarker for predicting immunotherapy response, the research team expanded their investigation to include samples from several international clinical trials. These trials specifically tested immunotherapy agents in patient cohorts diagnosed with the proficient subtype of bowel cancer. The results were compelling: individuals who responded favourably to immunotherapy exhibited significantly higher levels of CD74 compared to those who did not experience a positive outcome.
This evidence strongly suggests that measuring CD74 levels could serve as a reliable predictor of immunotherapy response in bowel cancer patients, irrespective of their tumour subtype. This is a paradigm shift, as it opens the door for individuals with the proficient subtype, who constitute the vast majority of cases and were previously excluded, to be considered for this potentially life-saving treatment.
Expert Perspectives and Future Implications
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 profound significance of these findings. "Immunotherapy drugs can be hugely successful for people with bowel cancer, 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," Professor Ciccarelli stated. "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."
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 advanced technologies. "Our work shows how state-of-the-art technologies coupled with computational analysis can address important clinical questions. As an early career research scientist, seeing the potential of our work to provide benefit to patients and their families is greatly rewarding," Clayton remarked.
The research team is actively collaborating with Cancer Research Horizons, an organization dedicated to translating scientific discoveries into clinical applications, to develop a CD74-based test suitable for routine clinical use. Furthermore, their future research agenda includes investigating the underlying mechanisms driving the overexpression of CD74 in macrophages and tumour cells, as well as exploring its potential as a biomarker in other cancer types.
Anna Kinsella, Science Engagement Manager at Cancer Research UK, emphasized the ongoing quest for more effective cancer treatments. "Immunotherapy treatments, such as immune checkpoint inhibitors, use the power of the immune system to fight cancer. Whilst these treatments benefit some people with bowel cancer, they aren’t effective for everyone," Kinsella explained. "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." She further added, "Understanding the biology of cancer is vital to unlocking better ways to prevent, detect and treat it, so that people can live longer, better lives free from the fear of cancer. That’s why at Cancer Research UK, discovery research is at the heart of everything we do."
The collaborative nature of this research is also noteworthy, with contributions from institutions including UCL, the University of Pisa, King’s College London, the Sarah Cannon Research Institute, and the Veneto Institute of Oncology, underscoring the global effort to advance cancer care.
A Timeline of Discovery and Potential Impact
The journey leading to this significant discovery likely spanned several years, a common trajectory for complex biological research. Initial explorations into the immune microenvironment of bowel cancer tumours would have begun, potentially years prior to the publication of the Cancer Cell paper. This phase would involve meticulous sample collection and basic immunological assays.
The advent of advanced technologies like spatial transcriptomics, which has seen significant development and accessibility in recent years, would have been a pivotal moment, enabling the researchers to move beyond bulk tissue analysis to understanding cellular interactions at a finer resolution. The period between the initial spatial transcriptomics experiments and the publication would have involved extensive data analysis, validation of findings across multiple datasets, and the crucial step of testing the CD74 marker in independent clinical trial cohorts. This validation phase is critical for establishing the robustness and clinical relevance of any potential biomarker. The publication in Cancer Cell in early 2024 marks a key milestone, signifying peer review and scientific consensus on the importance of these findings. The subsequent phase, currently underway, involves the translation of these research findings into a tangible clinical test, a process that can take several more years due to rigorous regulatory approval and standardization requirements.
Supporting Data and Broader Context
Globally, colorectal cancer is diagnosed in over 1.9 million people annually, and it is responsible for nearly one million deaths each year, according to the World Health Organization. In the UK, approximately 43,000 new cases are diagnosed each year. The economic and social burden of this disease is immense, underscoring the urgent need for more effective and broadly applicable treatments.
The current immunotherapy landscape for bowel cancer primarily revolves around immune checkpoint inhibitors, such as pembrolizumab and nivolumab. These drugs target proteins like PD-1 and PD-L1, which cancer cells can exploit to evade immune detection. While highly effective for a subset of patients, their inability to benefit a larger population, particularly those with the proficient subtype, represents a significant unmet medical need. The research into CD74 directly addresses this gap by identifying a potential predictor for response that transcends the current subtype-based eligibility criteria.
The implication of CD74 as a predictive marker is multifaceted. For patients with the proficient subtype, it offers a tangible pathway to accessing immunotherapy, potentially leading to improved survival rates and quality of life. For patients with the deficient subtype who do not respond to current therapies, identifying non-responders through CD74 testing could prevent them from undergoing potentially toxic treatments with no therapeutic benefit, allowing for earlier exploration of alternative treatment strategies.
Official Responses and Endorsements
The involvement of Cancer Research UK as a funding body and through its Science Engagement Manager’s statement highlights the national importance placed on this research. Their endorsement of "discovery research" as fundamental to advancing cancer treatment underscores the value of basic science in driving clinical innovation. The collaborative efforts with multiple academic and research institutions further signal a coordinated approach to tackling complex cancer challenges.
Broader Impact and Future Directions
The successful development of a CD74-based diagnostic test would represent a significant advancement in precision oncology for bowel cancer. It could lead to a paradigm shift in treatment selection, moving away from a more generalized approach to a highly personalized strategy guided by molecular biomarkers. This could not only improve patient outcomes but also optimize resource allocation within healthcare systems by ensuring that expensive and potentially toxic treatments are reserved for those most likely to benefit.
Beyond bowel cancer, the exploration of CD74’s role in other malignancies is a critical next step. If CD74 proves to be a universal predictor of immunotherapy response across various cancer types, its impact could be even more profound, revolutionizing cancer treatment on a much larger scale. The research team’s commitment to investigating the molecular mechanisms behind CD74 overexpression also holds promise for the development of novel therapeutic strategies that could directly target this pathway, potentially enhancing immunotherapy efficacy or even creating entirely new treatment modalities. The ongoing collaboration with Cancer Research Horizons is crucial for navigating the complex pathway from laboratory discovery to widespread clinical implementation, ensuring that this promising research translates into tangible benefits for patients worldwide.
