By Gilang Cahya 
Researchers have uncovered a critical link between age-related genetic changes in blood cells and the progression of cancerous tumors, revealing a phenomenon that significantly impacts patient prognoses. A groundbreaking study, published in the prestigious New England Journal of Medicine, demonstrates that the expansion of mutant blood cells, a process known as clonal hematopoiesis of indeterminate potential (CHIP), can infiltrate solid tumors and is directly associated with a higher risk of cancer relapse and mortality. This discovery, a collaborative effort involving institutions such as the Francis Crick Institute, UCL, Gustave Roussy, and Memorial Sloan Kettering Cancer Center (MSK), sheds new light on the intricate biological interplay between aging and cancer, offering potential avenues for future preventative therapies and treatment strategies.
The Growing Challenge of Age-Related Diseases
The global population is aging, with a steadily increasing proportion of individuals living into their later decades. This demographic shift brings with it a heightened prevalence of age-related diseases, including cancer and cardiovascular disorders. Understanding the underlying biological mechanisms that connect aging processes to these debilitating conditions is paramount for developing effective preventative measures and treatments. CHIP, a condition characterized by the accumulation of mutations in blood stem cells, has long been recognized as a consequence of both intrinsic aging processes and external environmental exposures. While its association with an increased risk of cardiovascular disease has been established, its specific role in the evolution and progression of solid cancers has remained an area requiring more in-depth investigation.
Unveiling the Link: CHIP in Solid Tumors
The comprehensive study, which analyzed blood samples from over 400 lung cancer patients enrolled in the Cancer Research UK-funded TRACERx and PEACE studies, alongside data from approximately 49,000 cancer patients from MSK, aimed to bridge this knowledge gap. Initial analyses of blood samples from these cohorts allowed researchers to identify individuals with CHIP mutations. A crucial correlation emerged: patients diagnosed with CHIP, irrespective of their age or the stage of their cancer at diagnosis, exhibited a shorter overall survival period. This finding underscored the detrimental impact of these age-related genetic alterations.
The research team then delved deeper, investigating whether these CHIP-associated mutations were also present within the lung tumors themselves, suggesting an infiltration of these mutated blood cells. This phenomenon, termed tumor-infiltrating clonal hematopoiesis (TI-CH), was identified in a significant 42% of patients with CHIP. The study’s most striking revelation was that it was TI-CH, rather than CHIP alone, that was the potent predictor of an increased risk of cancer relapse and mortality. This finding was further corroborated by data from the PEACE study, a postmortem investigation that examined metastatic sites – the primary cause of cancer-related deaths. The researchers observed that metastatic tumors frequently harbored these TI-CH mutations.
Not All Mutations Carry Equal Weight: The Role of TET2 and Myeloid Cells
To dissect the precise mechanisms by which TI-CH contributes to poor patient outcomes, the scientists meticulously examined the cellular composition of lung tumors. They discovered that patients with TI-CH had a notable expansion of myeloid cells, a specific type of immune cell. Myeloid cells play a complex role within the tumor microenvironment. Unlike certain immune cells that are programmed to recognize and combat cancer, myeloid cells are known to modulate inflammation and can actively promote tumor growth and dissemination.
Further investigation revealed that mutations affecting the TET2 gene, a critical regulator of blood cell production, were particularly prevalent in CHIP and were more likely to lead to the infiltration of mutant blood cells into tumors. By analyzing hundreds of single cells from the tumors of patients with TI-CH, the researchers confirmed that TET2 mutations were predominantly found within myeloid cells, with a much lower presence in other immune cell types.
In a pivotal experimental phase, the team collaborated with experts in blood cancer and CHIP within a Crick laboratory led by Dominique Bonnet. Together, they developed organoids – miniature laboratory-grown tumors – incorporating TET2-mutant myeloid cells. These experiments provided direct evidence that TET2-mutant myeloid cells actively remodel the tumor microenvironment and accelerate the growth of these organoids, thereby confirming their pro-tumorigenic role.
Broadening the Scope: TI-CH Across Diverse Cancers
The implications of these findings extend beyond lung cancer. In collaboration with researchers at Memorial Sloan Kettering Cancer Center, the team validated their results using an extensive dataset encompassing over 49,000 patients with a wide array of cancer types. The overarching conclusion remained consistent: the presence of TI-CH was an independent predictor of diminished survival. However, the prevalence of CHIP and TI-CH varied significantly across different cancer types. Notably, these mutations were found to be more common in cancers that are notoriously challenging to treat, such as lung cancer, head and neck cancer, and pancreatic cancer.
Future Directions and Potential for Intervention
The current research marks a significant step forward in understanding the complex interplay between aging and cancer. The immediate next steps for the research team involve confirming the direct causal contribution of CHIP to cancer outcomes and precisely delineating the mechanisms by which CHIP functionally contributes to the development of aggressive cancers.
Oriol Pich, a Postdoctoral Project Research Scientist at the Crick’s Cancer Evolution and Genome Instability Laboratory and a lead author on the study, emphasized the significance of the findings: "Our results demonstrate that blood cells harboring age-related mutations can infiltrate tumors and influence cancer evolution, leading to poorer outcomes for patients. This is particularly important because CHIP is a common, natural phenomenon of aging that is frequently observed in cancer patients."
Charlie Swanton, Deputy Clinical Director at the Crick, Chief Clinician at Cancer Research UK, and Chief Investigator for TRACERx, highlighted the novelty of the research: "This is the first time we’ve been able to observe at scale the interaction between two distinct types of clonal proliferations – age-related CHIP and cancer. This provides critical insights into how the aging process might impact cancer risk." He further expressed optimism for the future: "As we continue to unravel the most significant mutations that emerge during the aging process in bone marrow cells, and their impact on disease, we anticipate identifying opportunities for intervention and potentially even the prevention of certain age-related cancers."
This pioneering research was generously supported by Cancer Research UK and the National Institute of Health and Care Research UCLH Biomedical Research Centre, alongside other vital funding bodies. The collaborative nature of the study, bringing together expertise from leading institutions across the UK and the US, underscores the global effort to tackle the complex challenges posed by age-related diseases. The identification of TI-CH as a key driver of poor prognosis opens up new avenues for research into targeted therapies and diagnostic tools that could potentially identify patients at higher risk and guide more personalized treatment approaches.
