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Genomic Analysis of T cell Receptors Provides Novel Insights of Cancer Immunology in Lynch Syndrome Carriers

ABSTRACT: Lynch Syndrome (LS) provides the perfect context to understand DNA mismatch repair deficient (MMRd) carcinogenesis. LS carriers develop MMRd tumors with high neoantigen loads, which are shared by different LS tumors and recognized by T-cell receptors (TCRs) to trigger adaptive immunity. However, the TCR landscape in LS remains unexplored. Therefore, we performed TCR-sequencing in 277 blood samples from 102 LS cancer survivors, 130 LS previvors, and 45 controls, as well as three LS colorectal cancers, and 11 pre-cancers. For the first time, we found that up to 41% of the most expanded TCRβs from colorectal cancers and pre-cancers are detectable in the blood of several LS carriers, whereas these TCRs have minimal or no expansion in the blood of controls. Additionally, we developed a classification model that distinguishes LS carriers from controls with excellent performance using a set of 1,114 TCRβs that associates with all LS carriers, regardless of MMRd cancer history, and a set of 2231TCRβs that associates with LS previvors who have never developed cancer. This study is the first to describe circulating TCRβs that recognize neoantigens derived from colorectal cancers and pre-cancers in LS carriers, moving the field towards the identification of a blood based TCRβ cancer biomarker.

ORGANISM(S): Homo sapiens

PROVIDER: GSE289646 | GEO | 2026/03/02

REPOSITORIES: GEO

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