LONDON & NEW YORK – October 26, 2023 – In a significant scientific breakthrough, an international collaborative team of researchers has uncovered a critical link between the natural process of ageing and the aggressiveness of cancerous tumours. Scientists from the Francis Crick Institute, UCL, Gustave Roussy, and Memorial Sloan Kettering Cancer Center (MSK) have discovered that the expansion of mutant blood cells, a phenomenon inherently tied to ageing, can infiltrate cancerous tumours, a condition associated with significantly worse prognoses for patients across various cancer types.
This pivotal finding, published today in the prestigious New England Journal of Medicine, not only sheds new light on the complex interplay between age-related genetic changes and the evolution of cancer but also paves the way for novel diagnostic tools and potential therapeutic interventions. The study, which involved an extensive analysis of over 400 lung cancer patients and an astounding 49,000 patients with diverse cancer types, underscores the urgent need to understand and address the biological interface of age-related genetic alterations and diseases of ageing, such as cancer and cardiovascular disease.
Main Facts: A New Frontier in Cancer Prognosis
At the heart of this discovery lies "Clonal Haematopoiesis of Indeterminate Potential" (CHIP), a condition where blood stem cells, over time, accumulate specific mutations. Influenced by both the natural ageing process and various external environmental factors, CHIP has long been recognized for its association with an elevated risk of age-related disorders, including cardiovascular disease. However, its direct impact on the evolution and trajectory of solid cancers remained largely unexplored until now.
The collaborative research effort has meticulously detailed how these mutant blood cells, far from being inert passengers, actively infiltrate tumours. This infiltration creates a newly identified phenomenon termed "Tumour Infiltrating Clonal Haematopoiesis" (TI-CH). The researchers’ most compelling finding is that it is the presence of TI-CH, rather than CHIP in the bloodstream alone, that is strongly and independently associated with a greater risk of cancer relapse and, tragically, cancer-related death. This holds true irrespective of a patient’s age or the initial stage at which their cancer was diagnosed, marking TI-CH as a potent new prognostic indicator.
Specifically, the study highlights that TI-CH is characterized by an expansion of myeloid cells, a type of immune cell that, in this context, appears to foster an environment conducive to tumour progression rather than suppression. Furthermore, mutations in a particular gene, TET2, were found to be critically implicated, making blood cells more prone to infiltrating tumours and accelerating their growth. The sheer scale of the investigation, encompassing a vast patient cohort from the Cancer Research UK-funded TRACERx and PEACE studies, alongside an enormous dataset from MSK, lends immense weight and credibility to these groundbreaking conclusions.
Chronology of a Landmark Discovery
The journey to this significant revelation was a multi-faceted scientific endeavour, meticulously tracing the presence and impact of CHIP mutations from initial blood samples through to their active role within cancerous tumours.
Initial Examination and Prognostic Link: The research commenced with an initial examination of blood samples collected from over 400 patients diagnosed with lung cancer, as part of the ongoing Cancer Research UK-funded TRACERx and PEACE studies. This crucial first step allowed the research team to identify which patients harboured CHIP mutations in their circulating blood. When these genetic profiles were meticulously cross-referenced with comprehensive clinical data, a compelling pattern emerged: the presence of CHIP mutations in a patient’s blood was consistently associated with a shorter overall survival period. Crucially, this association held true even when accounting for confounding factors such as the patient’s age and the stage at which their cancer was initially diagnosed. This early finding signaled that CHIP was not merely an incidental age-related marker but a potentially significant player in cancer outcomes.
Unveiling Tumour Infiltrating Clonal Haematopoiesis (TI-CH): Building upon this initial correlation, the researchers embarked on a more granular investigation, delving deeper into the specifics of patients identified with CHIP. The central question was whether these specific mutations were merely circulating in the blood or if they were also present within the lung tumours themselves, potentially due to the infiltration of mutant blood cells. Their detailed analysis confirmed this hypothesis: in a striking 42% of patients with CHIP, the mutations were indeed detected within their lung tumours. This novel phenomenon was subsequently christened "Tumour Infiltrating Clonal Haematopoiesis" (TI-CH).
The discovery of TI-CH marked a critical turning point. The team meticulously demonstrated that it was the presence of TI-CH – the infiltration of these mutant cells into the tumour microenvironment – and not CHIP in the blood alone, that was significantly linked to a heightened risk of cancer relapse and, ultimately, cancer-related mortality. This distinction was paramount, suggesting a direct, active role for these mutant cells within the tumour itself.
Validation in Metastatic Disease: To further solidify these findings, the research team turned to samples from the PEACE study, a unique post-mortem investigation designed to map the spread of cancer, which is the primary cause of cancer death. The analysis of metastatic tumours found at these secondary sites unequivocally supported the earlier observations: these aggressive, disseminated tumours frequently contained TI-CH mutations, underscoring their presence in the most deadly forms of cancer progression.
Investigating the Mechanism: Myeloid Cells and TET2 Mutations: With TI-CH established as a critical prognostic factor, the next phase of the research focused on understanding the underlying biological mechanisms. Scientists investigated the cellular composition of lung tumours in patients with TI-CH. They observed a distinct expansion of myeloid cells, a specific type of immune cell, within these tumours. Unlike some immune cells that are specialized to recognize and eliminate cancer cells, myeloid cells have a complex role in the tumour microenvironment. They are known to regulate inflammation and, in many contexts, can paradoxically support tumour progression, growth, and spread, rather than fighting it.
Further genetic analysis revealed a crucial player: mutations affecting the TET2 gene. TET2 is an essential regulator of blood cell production, and the researchers discovered that when this gene was mutated, the resulting blood cells were significantly more likely to infiltrate the tumour. Through single-cell analysis of hundreds of cells from the tumours of two TI-CH patients, they confirmed that TET2 mutations were predominantly found within myeloid cells, rather than other immune cell types.
To experimentally validate these observations, the team collaborated with blood cancer and CHIP experts in Dominique Bonnet’s lab at the Crick. They engineered and grew organoids – miniature lung tumours – in the presence of TET2 mutant myeloid cells. These groundbreaking experiments conclusively showed that the TET2 mutant myeloid cells actively remodelled the tumour microenvironment, creating conditions that dramatically accelerated the growth of the tumour organoids.
Broader Validation Across Cancer Types: The final, expansive phase of the study involved a collaboration with researchers at Memorial Sloan Kettering Cancer Center in the US. This allowed the team to validate their findings using an unparalleled dataset of over 49,000 patients spanning a multitude of different cancer types. The results were remarkably consistent: the presence of TI-CH emerged as an independent predictor of shorter overall survival across this vast and diverse cohort. While the prevalence of CHIP and TI-CH varied among different cancer types, researchers noted that these mutations were more frequently observed in cancers notoriously known for being harder to treat, such as lung cancer, head and neck cancer, and pancreatic cancer. This broad validation cemented TI-CH’s status as a critical, pan-cancer prognostic factor.
Supporting Data: Deep Dive into CHIP, TI-CH, and the Tumour Microenvironment
The significance of this research lies not just in identifying a correlation, but in beginning to unravel the intricate biological mechanisms at play.
Understanding CHIP: Clonal Haematopoiesis of Indeterminate Potential (CHIP) is a common age-related condition. As individuals grow older, their haematopoietic stem cells (blood-forming stem cells) naturally accumulate genetic mutations. While many of these mutations are benign, some confer a survival advantage to the mutated cell clone, allowing it to expand and dominate a proportion of the blood cell population. This clonal expansion, even in the absence of a blood cancer, defines CHIP. Its prevalence increases with age, affecting approximately 10-15% of individuals over 65. Previously, CHIP was primarily linked to an increased risk of haematological malignancies and cardiovascular disease due to chronic inflammation. This study profoundly expands our understanding by demonstrating its direct impact on solid tumours.
The Crucial Distinction: CHIP vs. TI-CH: A key insight from this research is the critical distinction between having CHIP mutations in the circulating blood and having these mutant cells actively infiltrate the tumour, forming TI-CH. While CHIP itself was initially correlated with worse outcomes, the researchers definitively showed that the detrimental effect was primarily driven by TI-CH. This suggests that the physical presence and interaction of these mutant cells within the tumour microenvironment are what truly dictate the aggressive trajectory of the cancer. The observed infiltration rate of 42% in lung cancer patients with CHIP highlights that not all CHIP patients will develop TI-CH, making the infiltration event itself a crucial determinant of prognosis.
The Role of Myeloid Cells: The study’s focus on myeloid cells provides a critical mechanistic link. Myeloid cells are a diverse group of immune cells, including macrophages, neutrophils, and dendritic cells, which play vital roles in innate immunity, inflammation, and tissue repair. In the context of cancer, however, myeloid cells can be "re-educated" by the tumour microenvironment to support cancer growth. They can suppress anti-tumour immune responses, promote angiogenesis (formation of new blood vessels to feed the tumour), and facilitate metastasis. The finding that TI-CH is associated with an expansion of these pro-tumourigenic myeloid cells within tumours offers a tangible pathway through which age-related mutations can drive cancer aggression.
The TET2 Gene: A Molecular Lever: The identification of TET2 as a frequently mutated gene in TI-CH is particularly illuminating. The TET2 gene encodes an enzyme that plays a crucial role in epigenetic regulation, specifically in DNA demethylation, which influences gene expression. Mutations in TET2 are commonly found in CHIP and are also implicated in various myeloid blood cancers. Its role in promoting the infiltration of myeloid cells into tumours and subsequently accelerating tumour growth, as demonstrated in the organoid experiments, positions TET2 as a molecular lever through which age-related blood cell changes exert their detrimental effects on solid tumours. This finding opens avenues for targeting TET2 pathways in therapeutic strategies.
The Power of Large-Scale Data: The robustness of these findings is significantly bolstered by the scale and scope of the studies involved. The TRACERx (Tracking Cancer Evolution through Therapy) and PEACE (Post-mortem multi-organ analysis of cancer Evolution) studies, funded by Cancer Research UK, are pioneering efforts in understanding cancer evolution within living patients and at the time of death. These studies provided the detailed longitudinal data on lung cancer patients crucial for the initial discovery. The subsequent validation using MSK’s massive dataset of over 49,000 patients, covering a wide array of cancer types, transformed the findings from a lung cancer-specific observation into a broadly applicable principle in oncology, particularly for hard-to-treat cancers like pancreatic and head and neck cancers, where TI-CH was found to be more common.
Official Responses: Perspectives from the Frontlines of Research
The researchers involved expressed both the scientific significance and the potential clinical impact of their work.
Dr. Oriol Pich, Postdoctoral Project Research Scientist in the Crick’s Cancer Evolution and Genome Instability Laboratory, a lead author on the study, emphasized the direct implications for patient care: "Our results unequivocally show that blood cells carrying age-related mutations can infiltrate tumours and profoundly impact cancer evolution, leading to demonstrably worse outcomes for patients. This is an incredibly important revelation because CHIP is not a rare anomaly; it’s a natural and common phenomenon of ageing that is frequently observed in patients with cancer. Recognizing its active role within the tumour opens up new avenues for understanding and potentially mitigating cancer progression."
Professor Charlie Swanton, Deputy Clinical Director at the Crick, Chief Clinician at Cancer Research UK, and Chief Investigator for TRACERx, highlighted the groundbreaking nature of observing the interaction between two distinct biological processes: "This study represents a true first, allowing us to observe at an unprecedented scale the intricate interaction of two different types of ‘clonal proliferations’ – the age-related CHIP and the cancer itself. It provides profound insight into how the fundamental process of ageing might exert a significant and previously underappreciated impact on an individual’s cancer risk and progression. As we continue to meticulously piece together the complex picture of the most important mutations that evolve during the ageing process within cells originating from the bone marrow, and the precise impact they have in various diseases, our ultimate hope is to identify concrete opportunities for early intervention and, perhaps, even the prevention of some of these aggressive, age-related cancers."
This pioneering work was made possible through substantial support from key funding bodies, including Cancer Research UK and the National Institute of Health and Care Research UCLH Biomedical Research Centre, alongside additional funders, underscoring the collaborative spirit and investment required for such high-impact scientific endeavours.
Implications: Charting a Course for Future Cancer Care
The discovery of Tumour Infiltrating Clonal Haematopoiesis (TI-CH) represents a pivotal moment in oncology, carrying profound implications for future cancer research, diagnosis, and treatment strategies.
Novel Prognostic Biomarker: TI-CH emerges as a powerful new prognostic marker. Its independent association with shorter survival, regardless of age or cancer stage, suggests that screening for TI-CH in cancer patients could provide crucial information for risk stratification. Identifying patients with TI-CH could allow clinicians to tailor treatment plans, potentially opting for more aggressive therapies or closer monitoring for those at higher risk of relapse and metastasis.
Understanding Cancer Aggression: This research fundamentally alters our understanding of how cancer evolves and becomes aggressive. It demonstrates that the tumour is not an isolated entity but interacts dynamically with the host’s ageing immune system. The infiltration of mutant myeloid cells and their role in remodelling the tumour microenvironment provides a concrete mechanism by which age-related changes directly fuel cancer progression. This opens up entirely new research avenues to explore the precise molecular crosstalk between these mutant immune cells and cancer cells.
Targeted Therapies and Prevention: The identification of TET2 mutations as a key driver of TI-CH offers a potential therapeutic target. Developing drugs that specifically inhibit the pro-tumourigenic effects of TET2-mutant myeloid cells, or that prevent their infiltration into tumours, could represent a novel class of cancer therapies. Furthermore, if the direct causal link between CHIP/TI-CH and aggressive cancer development is firmly established, it might even lead to preventative strategies. Imagine screening for CHIP in older individuals and, if certain high-risk mutations are found, intervening to prevent the clonal expansion or infiltration before cancer even becomes aggressive.
Addressing Age as a Factor in Oncology: The study strongly reinforces the idea that age is not just a demographic factor in cancer but a biological one, with specific age-related molecular changes directly impacting disease trajectory. This necessitates a more integrated approach to geriatric oncology, where the unique biological landscape of older patients, including the presence of CHIP, is factored into treatment decisions.
Future Research Directions: The immediate next steps for this research are critical. Scientists aim to definitively confirm that CHIP directly contributes to adverse cancer outcomes through TI-CH. This will involve sophisticated preclinical models and further patient studies. Equally important is to meticulously detail the exact mechanisms by which CHIP functionally implicates itself in the development of aggressive cancers beyond the myeloid cell expansion and TET2 mutations already identified. Understanding these pathways could uncover additional targets for intervention.
In conclusion, this landmark study not only unravels a hidden layer of complexity in cancer biology but also offers a beacon of hope for improving outcomes for a growing proportion of the population affected by age-related cancers. By bridging the gap between ageing biology and cancer evolution, the research paves the way for a new era of personalized oncology, where age-related immune system changes are no longer overlooked but actively leveraged for smarter, more effective cancer care.
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