Spatiotemporal profiling of T cell repertoires in Lynch syndrome reveals convergent immune responses through neoplastic progression
- 1Institute of Cancer Research, London
Abstract
Surveillance of individuals with Lynch syndrome (LS), who are carriers of heterozygous inactivating mismatch repair (MMR) gene mutations that predispose to colorectal cancer, enables the study of tumour-immune coevolution during tumour initiation. Somatic loss of MMR activity in the LS colon leads to the accrual of cancer driver mutations, and also of neoantigens likely to generate an adaptive immune response. However, the spatial and temporal immune dynamics in colon and peripheral blood are uncharacterised. Here we show that the neoplastic evolution of mismatch repair deficient (MMRd) clones leads to large-scale and sustained reorganisation of the T-cell repertoire in colon and peripheral blood. We performed dense spatiotemporal profiling of T cell receptor (TCR) repertoires from 109 colonic biopsies (11 tumour samples, 98 normal bowel) from seven individuals, with eight matched blood repertoires. We additionally analysed 13 colorectal polyp repertoires from eight participants, 286 cross sectional blood repertoires from 242 participants (198 LS and 44 non-LS) and 52 longitudinal peripheral blood samples from 26 individuals with LS. We detected tumour-associated T cell clones, some of which were widely present in normal bowel tissue and also detectable in peripheral blood. Sequence similarity analysis revealed conserved TCR architectures across tissue compartments and recurrent clustering patterns between patients, that were not present in non-Lynch controls, consistent with convergent MMRd-associated antigen-driven immune selection. We identified systemic signatures associated with local tumour immune activity and revealed evidence of structured repertoire remodelling before overt malignancy. Longitudinal profiling revealed frequent turnover of low-abundance clonotypes, whereas highly abundant clonotypes persisted for several years. Collectively, our data defines the local and circulating TCR landscape associated with colonic neoplasia in LS, and provides a framework for LS blood-based immune monitoring, early interception and biomarker development.
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BibTeX
@misc{edwards2026spatiotemporal,
title = {{Spatiotemporal profiling of T cell repertoires in Lynch syndrome reveals convergent immune responses through neoplastic progression}},
author = {P. Edwards and O. Swinyard and T. Ronel and Y. Jiang and G. Nageswaran and C. Sakr and S. Yasmin and H. Grant and E. Smith and K. Braeutigam and K. Braeutigam and S. Varughese and P. Datt and A. Martinez and J. Fisher and B. Chain and K. K. Shiu and M. Jansen and A.-M. Baker and K. J. Monahan and T. A. Graham},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.06.756982},
url = {https://www.biorxiv.org/content/10.64898/2026.10.06.756982v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Spatiotemporal profiling of T cell repertoires in Lynch syndrome reveals convergent immune responses through neoplastic progression
AU - P. Edwards
AU - O. Swinyard
AU - T. Ronel
AU - Y. Jiang
AU - G. Nageswaran
AU - C. Sakr
AU - S. Yasmin
AU - H. Grant
AU - E. Smith
AU - K. Braeutigam
AU - K. Braeutigam
AU - S. Varughese
AU - P. Datt
AU - A. Martinez
AU - J. Fisher
AU - B. Chain
AU - K. K. Shiu
AU - M. Jansen
AU - A.-M. Baker
AU - K. J. Monahan
AU - T. A. Graham
PY - 2026
DA - 2026/10/06
PB - bioRxiv
DO - 10.64898/2026.10.06.756982
UR - https://www.biorxiv.org/content/10.64898/2026.10.06.756982v1
AB - Surveillance of individuals with Lynch syndrome (LS), who are carriers of heterozygous inactivating mismatch repair (MMR) gene mutations that predispose to colorectal cancer, enables the study of tumour-immune coevolution during tumour initiation. Somatic loss of MMR activity in the LS colon leads to the accrual of cancer driver mutations, and also of neoantigens likely to generate an adaptive immune response. However, the spatial and temporal immune dynamics in colon and peripheral blood are uncharacterised. Here we show that the neoplastic evolution of mismatch repair deficient (MMRd) clones leads to large-scale and sustained reorganisation of the T-cell repertoire in colon and peripheral blood. We performed dense spatiotemporal profiling of T cell receptor (TCR) repertoires from 109 colonic biopsies (11 tumour samples, 98 normal bowel) from seven individuals, with eight matched blood repertoires. We additionally analysed 13 colorectal polyp repertoires from eight participants, 286 cross sectional blood repertoires from 242 participants (198 LS and 44 non-LS) and 52 longitudinal peripheral blood samples from 26 individuals with LS. We detected tumour-associated T cell clones, some of which were widely present in normal bowel tissue and also detectable in peripheral blood. Sequence similarity analysis revealed conserved TCR architectures across tissue compartments and recurrent clustering patterns between patients, that were not present in non-Lynch controls, consistent with convergent MMRd-associated antigen-driven immune selection. We identified systemic signatures associated with local tumour immune activity and revealed evidence of structured repertoire remodelling before overt malignancy. Longitudinal profiling revealed frequent turnover of low-abundance clonotypes, whereas highly abundant clonotypes persisted for several years. Collectively, our data defines the local and circulating TCR landscape associated with colonic neoplasia in LS, and provides a framework for LS blood-based immune monitoring, early interception and biomarker development.
ER -