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Characterization of Circulating Neoantigen-Specific T Cell Responses and Their Public TCR Repertoires in Lynch Syndrome Carriers (scRNAseq)

ABSTRACT: Lynch syndrome (LS), a common hereditary cancer syndrome, provides a unique model to study immune surveillance at the earliest stages of tumorigenesis. A hallmark of LS carcinogenesis is the generation of highly immunogenic mutated neoantigens derived from insertion deletions, yet the transcriptomic states of the neoantigen-specific T cells that recognize them remain poorly characterized. Here, we characterized neoantigen-specific T cells from LS carriers using functional assays, single-cell RNA/TCR sequencing, and repertoire integration with existing data sets. Recurrent neoantigens elicited strong immune responses, with neoantigen-specific T cells mediating cytotoxicity against patient-derived tumor organoids. Single-cell analysis revealed oligoclonal expansions spanning effector and memory states with LS cancer survivors showing enrichment for metabolically exhausted subsets and previvor LS carriers retaining polyfunctional effectors. Cross-cohort analyses identified public clonotypes overlapping with tumor-infiltrating repertoire. These findings define the architecture of circulating neoantigen-specific immunity in LS and identify public TCRs as biomarkers for immune monitoring and immunoprevention.

ORGANISM(S): Homo sapiens

PROVIDER: GSE313248 | GEO | 2026/08/13

REPOSITORIES: GEO

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Characterization of Circulating Neoantigen-Specific T Cell Responses and Their Public TCR Repertoires in Lynch Syndrome Carriers (scTCRseq)

Project description:Lynch syndrome (LS), a common hereditary cancer syndrome, provides a unique model to study immune surveillance at the earliest stages of tumorigenesis. A hallmark of LS carcinogenesis is the generation of highly immunogenic mutated neoantigens derived from insertion deletions, yet the transcriptomic states of the neoantigen-specific T cells that recognize them remain poorly characterized. Here, we characterized neoantigen-specific T cells from LS carriers using functional assays, single-cell RNA/TCR sequencing, and repertoire integration with existing data sets. Recurrent neoantigens elicited strong immune responses, with neoantigen-specific T cells mediating cytotoxicity against patient-derived tumor organoids. Single-cell analysis revealed oligoclonal expansions spanning effector and memory states with LS cancer survivors showing enrichment for metabolically exhausted subsets and previvor LS carriers retaining polyfunctional effectors. Cross-cohort analyses identified public clonotypes overlapping with tumor-infiltrating repertoire. These findings define the architecture of circulating neoantigen-specific immunity in LS and identify public TCRs as biomarkers for immune monitoring and immunoprevention.

2026-08-13 | GSE313246 | GEO

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