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Discovery and validation of frameshift-derived neopeptides in Lynch syndrome: paving the way for novel cancer prevention strategies

  • 0Immunology, Hospital Clinic de Barcelona, Barcelona, Catalunya, Spain.
Journal for Immunotherapy of Cancer +

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April 20, 2025

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April 20, 2025

View abstract on PubMed

Summary

This summary is machine-generated.

Lynch syndrome patients have frameshift-derived neopeptides (FSDNs) that can be targeted by cancer vaccines. This study identified and validated FSDNs, showing they can elicit immune responses for cancer prevention in Lynch syndrome carriers.

Area Of Science

  • Oncology
  • Immunology
  • Genetics

Background

  • Lynch syndrome (LS) is linked to mismatch repair gene variants, causing microsatellite instability (MSI) and frameshift-derived neopeptide (FSDN) expression.
  • Effective colorectal cancer (CRC) prevention exists for LS, but strategies for most LS-related tumors are lacking.
  • Cancer vaccines targeting FSDNs present a promising avenue for immune interception in LS.

Purpose Of The Study

  • Identify and validate LS-related FSDNs for cancer prevention vaccine development.
  • Assess the immunogenicity of FSDNs in LS carriers.
  • Determine the potential of FSDNs for immune interception in LS.

Main Methods

  • In silico prediction of FSDNs with high coverage on common Human Leukocyte Antigen (HLA)-I and II alleles.
  • Validation of FSDN-associated mutations in colorectal adenomas (CrAD), endometrial cancers (EC), and CRC samples.
  • Immunogenicity assessment using interferon (IFN)-γ enzyme-linked immunospot and flow cytometry of tissue-infiltrating lymphocytes (TILs).

Main Results

  • 53 HLA-I and 45 HLA-II FSDNs were prioritized; 86.7% of FSDN-associated mutations were found in LS-CRC samples.
  • High mutation prevalence observed in CrAD (95%) and EC (77.5%); MSI cell lines transcribed 69.8% of FSDNs.
  • 71% of potential FSDNs elicited IFN-γ responses; 52% of LS-derived samples showed T-cell reactivity to an HLA-I neoantigen pool.

Conclusions

  • The identified FSDN set demonstrates optimal coverage in LS carriers.
  • These FSDNs can induce IFN-γ inflammatory responses in LS-derived TILs.
  • This provides a viable opportunity for developing LS cancer prevention vaccines.

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