Two papers published in Nature reveal long-disregarded functions of the thymus in adulthood, showing that the overall health of the organ impacts aging and risks for cardiovascular disease and cancer, as well as affecting response to immunotherapy in patients with cancer.
“The thymus has been overlooked for decades and may be a missing piece in explaining why people age differently, and why cancer treatments fail in some patients,” stated corresponding author of both papers Hugo Aerts, PhD, Director of the Artificial Intelligence in Medicine (AIM) Program at Mass General Brigham. “Our findings suggest thymic health deserves much more attention and may open new avenues for understanding how to protect the immune system as we age.”
Background and Study Methods
The thymus has traditionally been considered as essential for developing immune function in childhood and nonfunctional thereafter, especially since it shrinks with age and produces fewer new T cells. However, newer research has suggested that the thymus may have an important role in adulthood as well.
The research team conducted two studies to further examine the role of the thymus with the help of artificial intelligence (AI).
In the first study, they analyzed the size, shape, and composition of the thymus based on routine radiographic images to determine, with deep learning, a score of the overall health of a patient's thymus. Investigators evaluated the relationship between the health of the thymus and longevity and risk of cardiovascular disease and cancer. They used prospective data from the National Lung Screening Trial (n = 25,031) and the Framingham Heart Study (n = 2,581) to build a large dataset of asymptomatic adults.
In the second paper, the research team used a deep-learning framework to analyze computed tomography images from 3,476 patients with various cancers who were treated with immunotherapy.
Key Findings From First Paper
In the first paper, the researchers found that thymic health was very different across their study cohort. In the individuals from the National Lung Screening Trial, better thymic health was consistently associated with lower all-cause mortality, a lower incidence of lung cancer, and lower cardiovascular mortality—independent of age, sex, smoking, and comorbidities—in the 12 years of study follow-up. In the individuals from the Framingham Heart Study, better thymic health was significantly associated with lower cardiovascular mortality after adjusting for age, sex, and smoking.
Thymic health was associated with modifiable lifestyle factors such as smoking, obesity, and physical activity.
“Together, these findings reposition the thymus as a central regulator of immune-mediated aging and disease susceptibility in adulthood, highlighting its potential as a target for preventive and regenerative strategies to promote healthy aging and longevity,” the study authors concluded.
Key Findings From Second Paper
Among patients with non–small cell lung cancer, better thymic health was associated with lower risks for cancer progression and all-cause mortality, which was sustained with higher levels of PD-L1 expression and tumor mutation burden.
In an analysis of the prospective TRACERx lung cancer study, thymic health was positively associated with diversity of T-cell receptors and their excision circles; it was also linked with immune-system signaling pathways.
Findings were similar in patients with melanoma, breast cancer, and renal cancer.
“Together, these findings identify thymic health as a previously unrecognized, tumor-agnostic determinant of immunotherapy efficacy, with potential implications for patient stratification, treatment timing, and the development of immune-rejuvenating strategies in precision immuno-oncology,” the study authors concluded.
“Improving our understanding and monitoring of thymic health could eventually help physicians better assess disease risk and guide treatment decisions,” added Dr. Aerts.
The team is continuing to research the role of the thymus and how other factors may impact overall thymic health.
DISCLOSURES: This research received funding support from the National Institutes of Health, European Research Council, Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), Lundbeck Foundation, Novo Nordisk Foundation, and Savvaerksejer Jeppe Juhl og Hustru Ovita Juhl Research Stipend. For full disclosures of the study authors, visit nature.com.
