Spatiotemporal profiling of T cell repertoires in Lynch syndrome reveals convergent immune responses through neoplastic progression
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…
Lynch syndrome individuals, who carry inactivating mismatch repair gene mutations, provide an opportunity to study tumour-immune interactions during tumour initiation. Loss of MMR activity in the colon results in the accumulation of cancer-driving mutations and neoantigens that may trigger an adaptive immune response. However, the spatial and temporal dynamics of T cell populations in colon and blood tissues have not been well-characterized.
Our study revealed that the evolution of mismatch repair-deficient (MMRd) clones leads to a significant and persistent reorganization of the T-cell repertoire in both colon and peripheral blood. We conducted a dense spatiotemporal analysis of TCR repertoires from 109 colonic biopsies (including 11 tumour samples and 98 normal bowel specimens) from seven individuals, as well as eight matched blood repertoires.
Additionally, we examined 13 colorectal polyp repertoires from eight participants, 286 cross-sectional blood repertoires from 242 individuals (198 with LS and 44 without), and 52 longitudinal peripheral blood samples from 26 LS patients. We identified tumour-associated T cell clones, some of which were present in normal bowel tissue and in peripheral blood.
Through sequence similarity analysis, we found conserved TCR architectures across tissue compartments and recurrent clustering patterns that were unique to LS patients, suggesting convergent MMRd-associated antigen-driven immune selection. We also uncovered systemic signatures associated with local tumour immune activity and evidence of structured repertoire remodeling before the development of malignancy.
Longitudinal profiling showed frequent turnover of low-abundance clonotypes, while highly abundant clonotypes persisted for several years. Our findings provide a comprehensive picture of the local and circulating TCR landscape associated with colonic neoplasia in LS, and establish a framework for blood-based immune monitoring, early intervention, and biomarker development in LS patients.
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