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Introduction Lynch syndrome (LS), is caused by a germline pathogenic variant in one of the mismatch repair (MMR) genes. It is associated with a high lifetime risk of colorectal cancer (CRC) and other cancers. While tumours arising in LS are highly immunogenic due to mismatch repair deficiency (dMMR), it is unclear whether systemic immune responses are detectable in peripheral blood before or during neoplastic progression. Understanding blood-based immune signatures in LS could inform future non-invasive risk stratification and surveillance strategies.This study aimed to characterise peripheral blood T-cell receptor (TCR) repertoires in individuals with LS, with and without CRC, and compare them to non-LS controls.Methods Peripheral blood TCR repertoires were analysed in 161 individuals across four groups: LS without cancer (n = 106), non-LS healthy controls (n = 55), LS patients with dMMR CRC (n = 12), and non-LS patients with dMMR CRC (n = 19). Quantitative RNA-based TCR sequencing was performed using FUME-TCRseq. TCR diversity, clonotype number, and clonal expansion were analysed using the Immunarch R package and compared across each clinical group with paired colonoscopy findings. Longitudinal samples were analysed where available.Results LS patients had significantly fewer unique T-cell clonotypes than non-LS individuals (mean 3781 vs 4061, p = 0.0015) and markedly lower TCR diversity (1270 vs 2123, p = 8.6 × 10 -6 by Shannon entropy). Cancer-free non-LS controls exhibited significantly higher TCR diversity than cancer-free LS individuals (p = 1.3 × 10-6).Healthy LS patients demonstrated increased proportions of large (p = 5.5 × 10-8) and hyperexpanded (p = 1.5 × 10-9) T-cell clonotypes compared with non-LS healthy controls (figure 1), consistent with ongoing, persitent immune activation. Within LS, there was a stepwise increase in large and hyperexpanded clonotypes from individuals with normal colonoscopy findings, to those with high risk polyps (p=<0.05), and to those with CRC (p=<0.05).Longitudinal analysis showed that dominant circulating T-cell clonotypes persisted over several years in the majority of patients with repeated sampling (n = 10), indicating stable immune memory.Conclusions Peripheral blood T-cell repertoires in LS show reduced diversity and increased clonal expansion, consistent with chronic antigenic stimulation. The graded increase in clonal expansion from normal colonoscopy to polyps and cancer suggests that systemic immune responses may reflect colonic neoplastic burden in LS. The long-term persistence of expanded clonotypes supports durable immune memory and raises the possibility that blood-based immune profiling could contribute to future non-invasive biomarkers for risk stratification or surveillance in LS.Abstract O21 Figure 1More large and hyperexpanded clones present in patients with Lynch syndrome compared with non-lynch patients