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Study Links Thymus Gland Health to Longevity and Immunotherapy Outcomes in Adults

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The Thymus Gland: A New Frontier in Adult Health

A series of studies published in Nature and the New England Journal of Medicine have provided evidence challenging the long-held belief that the thymus gland becomes largely inactive after childhood.

Using artificial intelligence to analyze routine CT scans from large cohort studies, researchers found associations between thymic health and adult longevity, cardiovascular disease risk, cancer incidence, and response to cancer immunotherapy. The findings suggest the thymus may play a more significant role in adult immune function than previously understood.

Background on the Thymus

The thymus is a small organ located in the chest behind the breastbone. Its primary function is to produce and "educate" T cells, a type of white blood cell that helps the immune system identify and respond to pathogens, infections, and diseases.

After puberty, the thymus undergoes a process called involution, in which it progressively shrinks and its tissue is replaced by fat. Historically, this led many scientists to assume the organ had limited relevance to adult health. The recent studies now challenge this assumption by examining thymic characteristics in adulthood.

Study Methodology

Researchers from Mass General Brigham and collaborating institutions analyzed imaging data from over 25,000 adults in the National Lung Screening Trial (NLST) and more than 2,500 participants in the Framingham Heart Study (FHS). These cohorts involved a total of 27,612 participants who underwent computed tomography (CT) scans.

A deep learning model using convolutional neural networks was developed to quantify thymic health from the imaging data. The model generated a continuous thymic health score (0–100) based on the organ's size, shape, and tissue composition, serving as a proxy for functional status. Participants were categorized into low, average, and high thymic health groups.

Outcomes for all-cause mortality, lung cancer incidence, cardiovascular disease, and other health measures were analyzed over approximately 12 years. Statistical analyses adjusted for factors including age, sex, smoking status, and body mass index (BMI). Additional analyses examined associations between thymic health, metabolic markers, lifestyle habits, and inflammatory proteins.

Key Findings on Adult Longevity and Disease Risk

All-Cause Mortality

Individuals with higher thymic health scores had approximately a 50% lower risk of death from any cause compared to those with poorer thymic health. Over 12 years, 13.4% of participants in the high thymic health group died, compared to 25.5% in the low health group. These associations remained significant after adjusting for age and other health factors.

Cardiovascular Mortality

A 63% lower risk of cardiovascular death was observed among individuals with high thymic health scores in the NLST cohort.

Cancer Incidence and Mortality

Participants with healthier thymuses were found to have a lower risk of developing lung cancer. The incidence of lung cancer was 3.4% in the high thymic health group versus 5.3% in the low health group. Individuals with high thymic health scores had a 36% lower risk of developing lung cancer. Associations persisted after adjusting for smoking-related variables.

Additional Observations

Factors associated with poorer thymic health included chronic inflammation, smoking, and higher body weight. Lower thymic health was also associated with increased mortality from pulmonary, metabolic, and digestive diseases, suggesting a broader influence on disease resilience.

Historical Context: Thymectomy Study

A 2023 study published in the New England Journal of Medicine examined patients who had undergone surgical removal of the thymus (thymectomy). Within five years of surgery, these patients were more than twice as likely to die from any cause compared to similar patients who retained their thymus. Thymectomized patients were also twice as likely to develop cancer, and among those without pre-existing immune conditions, they had an increased risk of autoimmune disease.

Findings on Cancer Immunotherapy

In a separate analysis of over 1,200 cancer patients treated with immune checkpoint inhibitors, researchers evaluated the relationship between thymic health and treatment outcomes. The study included patients with various cancer types, including lung cancer, melanoma, breast cancer, and renal cancer.

Patients with higher thymic health scores had approximately a 37% lower risk of cancer progression and a 44% lower risk of death, even after accounting for differences in patient characteristics, tumor types, and treatments.

Additional analyses in an independent cohort (TRACERx) indicated that radiographic quantification of thymic health reflects thymic functionality and immune competence. Researchers found higher levels of sjTRECs (a marker of thymic activity) and increased T cell diversity in patients with high thymic health.

Thymic health was prognostic in patients with advanced Non-Small Cell Lung Cancer (NSCLC) receiving immunotherapy, including those who had received prior cytotoxic chemotherapy. Effect sizes were strongest in the first-line treatment setting. The study suggests thymic health provides prognostic value independent of established biomarkers such as PD-L1, potentially by capturing host immune competence.

Limitations and Cautions

Researchers have stated that these findings require confirmation in future studies and that the imaging method for measuring thymic health is not yet ready for routine clinical use.

Specific limitations include:

  • The study populations were predominantly White, which may limit generalizability across diverse ethnic populations.
  • The NLST cohort included heavy smokers, which may affect generalizability to non-smoking populations.
  • The studies did not test whether modifying lifestyle factors directly improves thymic function.
  • As an observational study design, it does not establish causality between thymic health and the observed outcomes.
  • The study design lacked a matched non-immunotherapy comparator, preventing direct assessment of predictive implications for treatment selection.
  • Universal thresholds for thymic health scores have not been established; analyses were performed using population-specific thresholding.
  • Generalizability across different CT scanners, institutions, and countries must be demonstrated.

Ongoing Research

Scientists are investigating other factors that might impact thymic health, including unintended radiation exposure to the thymus in lung cancer patients. Researchers are also working to engineer a human thymus in the laboratory, with aims including aiding transplant tolerance and potentially slowing natural thymic decline.

Funding

Support for this research was provided by the National Institutes of Health, European Research Council, Deutsche Forschungsgemeinschaft (DFG), Lundbeck Foundation, Novo Nordisk Foundation, and Savvaerksejer Jeppe Juhl og Hustru Ovita Juhl Research Stipend.