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

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.