Genomic analysis of T Cell receptors reveals lynch syndrome specific immune signatures

Abstract

Abstract Lynch Syndrome (LS) provides the perfect context to understand DNA mismatch repair deficient carcinogenesis, which is characterized by neoplastic lesions with high rates of shared neoantigens eliciting adaptive immunity through T cell receptor (TCR) recognition. However, the TCR landscape in LS carriers remains unexplored. Here, we perform TCR sequencing of 277 blood samples from LS cancer survivors, previvors, and controls, as well as matching colorectal cancers and pre-cancers. We show that up to 41% of the most expanded TCRβs from colorectal neoplasms are detectable in the blood of LS carriers, while showing minimal expansion in controls. In addition, we develop and validate a classification model that distinguishes LS carriers from controls using circulating TCRβs signatures associated with LS independent of thecancer history and with cancer-free LS previvors. Together, our findings characterize circulating and tissue TCRβs associated with LS, thus representing a step toward identifying blood-based TCR biomarkers for immune surveillance.