By Lina carolina 
The immune systems of cancer patients are highly disrupted, with those who have a higher number of immune cells in their blood having a better survival rate, finds a new study that uses a pioneering technique developed by researchers at UCL and the Francis Crick Institute. This groundbreaking development, detailed in the prestigious journal Nature Genetics, introduces Immune Lymphocyte Estimation from Nucleotide Sequencing (ImmuneLENS), a novel tool that enables scientists to quantify the proportion of T cells and B cells—key players in the immune response—directly from whole genome sequencing (WGS) data. This marks a significant leap forward, as previously, such precise immune cell profiling from WGS was not feasible.
A New Frontier in Immune System Profiling
Whole genome sequencing, a process that meticulously maps an individual’s complete DNA blueprint from a blood sample, has revolutionized our understanding of human biology. It offers a comprehensive record of genetic instructions, allowing scientists to identify genetic variations, understand disease mechanisms, and monitor the body’s fight against illness. The ImmuneLENS tool leverages this rich data, providing an unprecedented window into the immune landscape of individuals, particularly in the context of cancer.
The research team harnessed ImmuneLENS to analyze a colossal dataset of over 90,000 WGS samples from the 100,000 Genomes Project. This ambitious initiative, a collaboration between Genomics England and NHS England, has amassed genetic data from a diverse population, encompassing both healthy individuals and those battling cancer. The sheer scale of this dataset provided an unparalleled opportunity to identify robust patterns and correlations.
Immune Cell Balance: A Crucial Prognostic Factor
The findings from this extensive analysis are striking. Cancer patients, on average, exhibited a lower proportion of T cells circulating in their bloodstream compared to their healthy counterparts. More critically, the study established T cell proportion in the blood as a potent predictor of cancer prognosis. Patients with a higher percentage of T cells in their blood demonstrated a remarkable 47% reduction in mortality over a five-year period following surgery. This correlation remained statistically significant even after accounting for crucial confounding factors such as patient age, cancer stage, and across all investigated cancer types.
These biological markers, easily quantifiable and readily available, could be integrated into existing genetic diagnostic tests. This integration would equip clinicians with richer, more actionable information, empowering them to tailor treatment plans with greater precision and efficacy.
Professor Nicholas McGranahan, a senior author of the study from the UCL Cancer Institute, emphasized the paradigm shift this technique represents. "Most immune system analysis until now has focused on the tumour itself," he stated. "So the results we’re seeing using this new technique—which examines the number of immune cells in a person’s blood—are of considerable interest. What’s going on with immune cells in the blood seems to have a huge impact on cancer survival and may be able to predict how long a cancer patient will survive better than the number of T cells in the tumour alone."
Professor McGranahan further elaborated on the transformative potential of ImmuneLENS. "There have been hints in previous research that this might be important, but being able to analyse immune system information at this scale is game-changing," he remarked. "The ability to compare immune cell changes in the blood and to what’s happening in the tumour environment opens up new avenues for cancer research, as well as healthcare research more widely."
The clinical implications are profound. "In terms of patient diagnosis and treatment, knowing whether a patient has relatively high or low numbers of immune cells in the blood, and how this corresponds to their prognosis, could help clinicians to decide on the best course of treatment for the individual," Professor McGranahan added.
Understanding Cancer’s Immune Evasion
Cancer, at its core, is a disease driven by genetic mutations that disrupt normal cellular function. While the immune system is designed to detect and eliminate cells with dangerous mutations, cancer cells often develop sophisticated mechanisms to evade this immune surveillance, thereby compromising the body’s natural defenses. A comprehensive understanding of both the localized immune environment surrounding a tumor and the broader systemic immune response is therefore paramount for deciphering cancer’s progression and predicting patient responses to therapies.
Large-scale genomic projects like the 100,000 Genomes Project have been instrumental in providing researchers with unprecedented access to the full spectrum of genetic alterations in both healthy and cancerous cells. However, precisely quantifying the immune cell composition within the tumor microenvironment and the wider immune system has remained a significant challenge—until now.
ImmuneLENS builds upon earlier advancements, including a 2021 method that allowed for the calculation of T cell proportions in whole exome sequencing data. This latest iteration, however, offers a more comprehensive analysis by incorporating whole genome sequencing and extending its capabilities to B cells.
Age-Related Immune Decline and Early Cancer Detection
The study also shed light on the interplay between aging, cancer, and immune cell populations. It is well-established that the proportion of immune cells in the blood naturally declines with age in healthy individuals. However, the researchers observed that this decline appears to occur earlier and more rapidly in individuals diagnosed with cancer. This accelerated immune aging in cancer patients warrants further investigation.
Interestingly, this effect was more pronounced in male cancer patients compared to their female counterparts. The underlying reasons for these observed sexual differences remain unclear and require further research to determine if they have a significant impact on overall cancer survival rates.
Furthermore, the study revealed a compelling observation regarding B cells. Individuals who appeared healthy at the time of their blood sample collection for sequencing, but subsequently developed cancer, exhibited lower-than-average levels of B cells in their blood. This finding suggests a potential pre-clinical indicator of disease. These diminished B cell levels could be indicative of undiagnosed early-stage cancer or pre-cancerous immune system changes, possibly serving as an early warning sign or even a contributing factor to cancer development.
This discovery holds significant promise for future cancer early detection strategies and for refining clinicians’ ability to predict how patients might respond to various treatments.
Dr. Robert Bentham, the first author of the study from the UCL Cancer Institute, drew an insightful analogy to explain the novelty of their approach. "Lots of approaches that measure immune cells from genetic data are like looking for a needle in a haystack," he explained. "Our approach in this study instead looks at the haystack itself and asks how the presence of immune cells changes its overall shape. It’s a different, more efficient way of finding the needle."
He continued, "One of the things this will allow us to do is to build significant immune datasets using data we already have from the many large-scale WGS cohorts but haven’t been able to interrogate until now. It will allow researchers to explore what’s happening in the immune system during health and disease, not just in cancer but potentially in many areas of medicine."
Distinguishing B Cell Subtypes for Prognostic Value
The ImmuneLENS method also offers the advantage of easily distinguishing between different subtypes of B cells. As B cells mature, they specialize to produce specific types of antibodies, proteins crucial for neutralizing harmful agents like viruses, bacteria, and mutated cells. The researchers leveraged this specialization process to identify and classify B cells with remarkable accuracy.
When applied to WGS data, this refined analysis revealed that B cells producing IgM/D antibodies—typically the first type of antibody produced upon encountering a foreign antigen—were the only B cell subset consistently associated with improved survival outcomes in cancer patients. This suggests that these specific B cells may play a pivotal role in anti-tumor immunity. Their consistent presence and association with better prognoses also position them as promising new biological markers for cancer diagnosis and potential therapeutic targets for future research.
Translating Discoveries into Clinical Practice
The researchers are eager to translate these significant findings into tangible clinical benefits. They believe these newly identified biological markers can be seamlessly integrated into the current suite of diagnostic tests for cancer patients at no additional cost. Professor McGranahan and his team have already secured a Cancer Research UK (CRUK) funded Biomarker Project Award to expedite this crucial translation into clinical practice.
This integration could be particularly impactful in predicting a patient’s response to immunotherapy. While the proportion of T cells within a tumor is a known biomarker for immunotherapy efficacy, it cannot be routinely measured using standard genomic tests. ImmuneLENS offers a viable alternative, enabling this crucial information to be obtained from blood samples.
Dr. Nisharnthi Duggan, Research Information Manager at Cancer Research UK, expressed enthusiasm for the ongoing work. "Cancer Research UK is pleased to support this ongoing work investigating whether measuring immune cell levels in our blood can help predict cancer survival," she commented. "We’re living in a golden age of research where we can use patient data in sophisticated ways to help us better understand cancer and how to beat it."
Dr. Duggan added, "Further research is needed, but this could one day become a tool to help doctors personalize treatment for people with cancer."
This pioneering research is an integral part of the Cancer Research UK-funded TRACERx project, a comprehensive study investigating the evolutionary and genomic basis of cancer. The success of this study was made possible through privileged access to the invaluable data and findings generated by the 100,000 Genomes Project, meticulously managed by Genomics England. The collaborative spirit and the availability of large-scale genomic datasets have been fundamental to unlocking these critical insights into cancer biology and the intricate workings of the human immune system. The implications for personalized medicine and early cancer detection are substantial, paving the way for more effective and tailored cancer care in the future.
