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

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: GSE313246 | 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 (scRNAseq)

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 | GSE313248 | GEO

Genomic Analysis of T cell Receptors Provides Novel Insights of Cancer Immunology in Lynch Syndrome Carriers

Project description:Lynch Syndrome (LS) provides the perfect context to understand DNA mismatch repair deficient (MMRd) carcinogenesis. LS carriers develop MMRd tumors with high neoantigen loads, which are shared by different LS tumors and recognized by T-cell receptors (TCRs) to trigger adaptive immunity. However, the TCR landscape in LS remains unexplored. Therefore, we performed TCR-sequencing in 277 blood samples from 102 LS cancer survivors, 130 LS previvors, and 45 controls, as well as three LS colorectal cancers, and 11 pre-cancers. For the first time, we found that up to 41% of the most expanded TCRβs from colorectal cancers and pre-cancers are detectable in the blood of several LS carriers, whereas these TCRs have minimal or no expansion in the blood of controls. Additionally, we developed a classification model that distinguishes LS carriers from controls with excellent performance using a set of 1,114 TCRβs that associates with all LS carriers, regardless of MMRd cancer history, and a set of 2231TCRβs that associates with LS previvors who have never developed cancer. This study is the first to describe circulating TCRβs that recognize neoantigens derived from colorectal cancers and pre-cancers in LS carriers, moving the field towards the identification of a blood based TCRβ cancer biomarker.

2026-03-02 | GSE289646 | GEO

Identification and Validation of Frameshift Neoantigens for Mismatch-Repair Deficient Lynch Syndrome

Project description:Lynch syndrome (LS) patients develop DNA mismatch repair deficient tumors which generate high loads of neoantigens (neoAgs), thus constituting a well-defined population that can benefit from cancer immune-interception strategies, including neoantigen-based vaccines. Using paired whole-exome sequencing and mRNAseq of colorectal cancers (CRC) (n=13) and pre-cancers (n=61) from our LS patient cohort (N=46), we performed in-silico prediction and immunogenicity ranking of highly recurrent frameshift-neoags, followed by their in-vitro validation. We described the somatic mutation landscape in all cancers and pre-cancers, and showed that mutation burden is positively correlated with neoAgs load. Furthermore, our in-vitro validation showed a 65% validation rate of our top 100 predicted neoags. Consistent with neoAgs burden, our transcriptomic results revealed increased infiltration of CD8+ and CD4+ T-cells in microsatellite unstable samples. Overall, our neoAgs catalog and all other findings, improve our understanding of cancer development in LS and guide us towards the advancement of immunoprevention vaccine strategies.

2024-03-25 | GSE224707 | GEO

Mis-splicing derived neoantigens and cognate T cell receptors in splicing factor mutant leukemias

Project description:Mutations in RNA splicing factors are prevalent across cancers and generate recurrently mis-spliced mRNA isoforms. Here we identified a series of bona fide neoantigens translated from highly stereotyped splicing alterations promoted by neomorphic, leukemia-associated somatic mutations in the splicing machinery. We utilized feature-barcoded peptide-MHC dextramers to isolate neoantigen-specific T cell receptors (TCR) from both healthy donors and patients with leukemia. While circulating neoantigen-specific CD8+ T cells were identified in patients with active disease, they were dysfunctional with reduced inflammatory response gene signatures. In contrast, donor CD8+ T cells with tumor-reactive TCRs were present following curative allogeneic hematopoietic cell transplant. T cells engineered with TCRs recognizing an SRSF2 mutant-induced neoantigen in CLK3 resulted in specific recognition and cytotoxicity of SRSF2 mutant leukemia. These data identify RNA mis-splicing derived neoantigens and neoantigen-specific TCRs across patients and provide proof-of-concept to genetically redirect T cells to public mis-splicing derived neoantigens in myeloid leukemias.

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2022-12-01 | GSE183981 | GEO

Evaluation of splicing alterations in mice treated with RECTAS.

Project description:Aberrant pre-mRNA splicing events in tumor cells generate tumor-specific splice junctions, translating potential neoantigens. RNA-seq was performed to examine whether a small molecule compound RECTAS affect splice patterns followed by neoantigen repertoire in mouse colon, lung, and liver tissues.

2022-12-01 | GSE205137 | GEO

Exercise-associated epigenetic remodeling and TCR repertoire dynamicsin Lynch Syndrome carriers (MEDIP-seq)

Project description:Lynch Syndrome (LS) carriers are at elevated cancer risk. Recent data suggest exercise as a non-pharmacologic preventive strategy, yet the epigenetic and immunological mechanisms underlying its protective effects in this population remain unclear. Here, we perform integrative multi-omics profiling of DNA methylation, gene expression, and the T cell receptor (TCR) repertoire in LS carriers participating in a 52-week aerobic cycling intervention. We identify compartment-specific DNA methylation changes, including innate immune activation in cfDNA and oncogenic pathway repression in tissue. Transcriptomic integration highlights ISL1 as a key exercise-repressed gene and FLCN as a CRC-associated methylation target. TCR analysis reveals increased systemic repertoire diversity and tissue-specific clonal convergence, thus suggesting antigen-driven recruitment. These findings uncover epigenetic and immune remodeling as potential mechanisms of exercise-mediated protection in LS.

2026-08-03 | GSE310884 | GEO

Exercise-associated epigenetic remodeling and TCR repertoire dynamicsin Lynch Syndrome carriers (RRBS)

2026-08-03 | GSE309783 | GEO

A Study of Personalized Neoantigen Cancer Vaccines

Project description:The purpose of this study is 1) to evaluate the feasibility of manufacturing a patient-specific neoantigen cancer vaccine, which involves predicting the patient’s neoantigens and generating a vaccine that encodes the predicted neoantigens; and, 2) to identify and select patients who may be eligible for a shared neoantigen cancer vaccine where their tumor contains a specific shared mutation and who have the correct HLA allele capable of presenting the neoantigen derived from the tumor-specific mutation.

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WGS for B16-OVA and 4T1 murine cancer cell lines

Project description:Whole Genome Sequencing of the murine breast cancer cell line 4T1 and of the murine melanoma cell line B16-ova was carried out with the aim of identifying somatic mutations. We also ran deep Mass Spectrometry proteomics analysis on the same cell lines, aiming to determine which somatic mutations carry over to the protein expression level. Further, we tested these cancer specific protein epitopes (putative neoantigens) for immunogenicity using mouse models. Finally, the putative neoantigens that showed good immunogenic potential were used in tumor growth control experiments with mice engrafted with the two tumor cell lines. In these experiments we tested whether cancer vaccines based on individual neoantigen peptides (MHC-I) restricted the growth of the tumor compared to adequate controls. The overall aim of the project is to validate the ability of our multi-omics/bioinformatics pipeline to identify and deliver neoantigens that can be used to suppress tumor growth. File names Sample names P10859_101_S1_L001_R1_001_BHKWV3CCXY 4T1_S1_L001_R1_001_BHKWV3CCXY P10859_101_S1_L001_R2_001_BHKWV3CCXY 4T1_S1_L001_R2_001_BHKWV3CCXY P10859_101_S1_L002_R1_001_BHKWV3CCXY 4T1_S1_L002_R1_001_BHKWV3CCXY P10859_101_S1_L002_R2_001_BHKWV3CCXY 4T1_S1_L002_R2_001_BHKWV3CCXY P10859_102_S2_L003_R1_001_BHKWV3CCXY B16-OVA_S2_L003_R1_001_BHKWV3CCXY P10859_102_S2_L003_R2_001_BHKWV3CCXY B16-OVA_S2_L003_R2_001_BHKWV3CCXY P10859_102_S2_L004_R1_001_BHKWV3CCXY B16-OVA_S2_L004_R1_001_BHKWV3CCXY P10859_102_S2_L004_R2_001_BHKWV3CCXY B16-OVA_S2_L004_R2_001_BHKWV3CCXY

2024-01-31 | E-MTAB-13635 | biostudies-arrayexpress

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