Abstract 5083: Investigating the impact of T cell receptor repertoire diversity on cancer outcome

Abstract T cells are key effector cells in the adaptive immune system, playing a central role in the defense against pathogens. However, as we age, T cells undergo functional decline due to immunosenescence, the gradual decay of the immune system with age. This decline negatively affects the function and composition of immune cells, leading to an increased susceptibility to age-related diseases, such as cancer. We hypothesized that characterization of the peripheral blood T cell receptor (TCR) repertoire has the potential to provide insights into the current state of the immune system and serve as a biomarker for cancer progression. To investigate this, we analyzed the peripheral blood TCR repertoire in 5441 non-cancer patients and 450 cancer patients, utilizing sequencing data of the TCR-β chain from multiple cohorts obtained locally and from public sources. In both cancer and non-cancer patients, we observed a decline in the percentage of non-expanded clones, averaging approximately 4.6% (P = 2.15 × 10-8) and 3.5% (P < 2 × 10-16) for every 10-year increase in age, respectively. This decline was accompanied by a proportional increase in the expanded T cell clones with advancing age. Analyses of TCR-β diversity across age groups revealed that, among older individuals, males exhibited lower diversity than females in both non-cancer (P = 4.9 ×10-5) and cancer patients (P = 5.3 × 10-5). Additionally, investigating the relationship between tumor stage and TCR-β diversity showed that lower diversity correlates with more advanced tumor stages. Our results suggest that low TCR diversity represents reduced immune competency and a limited ability to prevent cancer progression. Citation Format: Naja Lange, Asbjørn Kjær, Randi Istrup Juul, Iver Nordentoft, Lars Dyrskjøt, Nicolai Juul Birkbak. Investigating the impact of T cell receptor repertoire diversity on cancer outcome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5083.