T Cell Receptor Diversity, Cancer and Sex: Insights from 30,000 TCR β Repertoires
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Cancer is a widespread disease claiming millions of lives each year, yet the relationship between cancer risk and age-related immune system decline (i.e., immunosenescence), specifically the ability of T cells to detect and eliminate cancerous cells, remains poorly understood. Here, we analyze T cell receptor (TCR) β repertoires from ∼30,000 subjects demonstrating that TCR diversity—a key measure of immunocompetency—systematically declines between the ages of 20 and 80 years. Notably, this decline occurs 11 years later in females compared to males and coincides with their lower incidence of cancer, rein-forcing the link between TCR diversity and cancer risk. Thus, we model rising cancer incidence with age as a product of accumulating mutations and the increasing probability that cells harboring these mutations evade immune detection due to loss of TCR diversity. Our analysis suggests that both of these processes significantly contribute to the risk of cancer and that lower cancer incidence in females is due to the delayed onset of immunosenescence. Our results highlight the importance of understanding immunosenescence in carcinogenesis, potentially providing new opportunities for immunotherapies targeting an aging immune system and for personalized care leveraging TCR diversity as a biomarker.
