Duzagac et al. characterized circulating neoantigen-specific T cells in Lynch syndrome (LS) carriers using functional assays, single-cell RNA/TCR sequencing, and integration with existing TCR datasets. Cancer-free LS carriers retained polyfunctional effector and tissue-surveillance states, whereas cancer survivors showed glycolytic, stress-associated, and exhausted T cell states. Recurrent frameshift neoantigens elicited strong T cell responses and tumor organoid killing. Public neoantigen-specific TCRs showed clonal expansion and were shared across blood, pre-cancer, and tumor tissues. Reconstructed TCRs mediated HLA-restricted tumor recognition.
Contributed by Shishir Pant
(1) Duzagac F (2) Deng N (3) Wang J (4) Nagaraju S (5) Steinberger P (6) Reuben A (7) Sinha KM (8) Vilar E
Duzagac et al. characterized circulating neoantigen-specific T cells in Lynch syndrome (LS) carriers using functional assays, single-cell RNA/TCR sequencing, and integration with existing TCR datasets. Cancer-free LS carriers retained polyfunctional effector and tissue-surveillance states, whereas cancer survivors showed glycolytic, stress-associated, and exhausted T cell states. Recurrent frameshift neoantigens elicited strong T cell responses and tumor organoid killing. Public neoantigen-specific TCRs showed clonal expansion and were shared across blood, pre-cancer, and tumor tissues. Reconstructed TCRs mediated HLA-restricted tumor recognition.
Contributed by Shishir Pant
ABSTRACT: Lynch syndrome (LS), a common inherited genetic condition predisposing to cancer, 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 neoantigens, yet the transcriptomic states of the T cells that recognize them remain poorly understood. Here, we characterize neoantigen-specific T cells from LS carriers using functional assays, single-cell RNA/T cell receptor (TCR) sequencing, and repertoire integration with existing large datasets. Recurrent neoantigens elicit strong immune responses, with neoantigen-specific T cells mediating cytotoxicity against tumor organoids. Single-cell analysis reveals oligoclonal expansions spanning effector and memory states with enrichment for exhausted subsets among cancer survivors and retention of polyfunctional effectors in cancer-free carriers. Cross-cohort analysis identifies public TCR clonotypes in circulation that overlap with pre-cancer and tumor tissue repertoires. Together, these findings define the architecture of circulating neoantigen-specific immune memory in LS and highlight public TCRs as candidates for immune monitoring and immunoprevention.
Author Info:
(1) Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (2) Department of Clinical Cancer Prevention, The University of T
exas MD Anderson Cancer Center, Houston, TX, USA. (3) Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (4) Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (5) Institute of Immunology, Medical University of Vienna, Vienna, Austria. (6) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (7) Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (8) Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: evilar@mdanderson.org.
Citation: Cell Rep Med 2026 Sep 18 103057 Epub09/18/2026
