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.
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Data availability
The TCRseq data generated in this study are publicly available in Zenodo (https://zenodo.org/records/13141052) and the scRNA-seq data generated in this study are publicly available in GEO under accession number GSE289646 Source data are provided with this paper.
Code availability
The code used in this study is publicly available at https://github.com/Vilarlab-MDACC/LS_TCR.
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Acknowledgements
We thank the patients and their families for their participation. We thank the staff of the CPRIT Single Cell Genomics Core at MD Anderson Cancer Center for the assistance with single-cell TCR and RNA sequencing and the staff of the Advanced Technology Genomics Core and Cancer Genomics Laboratory at MD Anderson Cancer Center for their initial assistance in sequencing libraries generated from tissues and blood samples. We would like to acknowledge the support from the University of Kansas Medical Center’s Biospecimen Repository Core Facility staff including Maura Kluthe, Alex Webster, Eric Johnson, and Lauren DiMartino for identifying, collecting, and processing human specimens; the support from Araceli Garcia Gonzalez, Jacklyn Thompson and Pragya Mishra for their assistance in identifying, consenting, collecting and processing human specimens from the MD Anderson cohort. The authors are grateful to Karen Colbert for her editorial assistance in the preparation of the manuscript.
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N.D. conducted the bioinformatic pipelines for TCR classifier development. F.D. performed single-cell sequencing and immunological assays. A.M.B. initiated the study, performed bulk TCR sequencing and bioinformatic analyses, and drafted the initial manuscript. N.D., F.D., and K.M.S. contributed to data analysis, manuscript review, editing, and finalization. M.W.T. performed pathological interpretation of tissue section specimens. L.R.U., S.T., L.R., P.M.L., Y.N.Y., and E.V. provided clinical samples and associated clinical information. F.M., M.P., and G.C. critically reviewed the manuscript and provided clinical samples from Spain. A.B. provided clinical samples from Kansas. S.K., P.S., G.A.L., and A.R. provided critical input on study design. E.V. led conceptualization, supervised the study, secured funding, and contributed to data analysis, manuscript review, and editing. E.V. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
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Eduardo Vilar (EV) had a consulting or advisory role with Janssen Research and Development, Recursion Pharma, Nouscom, Abbvie, Moderna, Permanence Bio and Parabilis. EV has received research support from Janssen Research and Development and Nouscom. EV has equity in Permanence Bio. The remaining authors declare no competing interests.
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Nature Communications thanks Kazuhiko Hashimoto, Santiago Carmona and the other anonymous reviewers for their contribution to the peer review of this work. [A peer review file is available].
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Deng, N., Duzagac, F., Bolivar, A.M. et al. Genomic analysis of T Cell receptors reveals lynch syndrome specific immune signatures. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71243-z
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DOI: https://doi.org/10.1038/s41467-026-71243-z
