Identification of an HLA-A0201-restricted CTL epitope generated by a tumor-specific frameshift mutation in a coding...

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• Deficient DNA mismatch repair leads to microsatellite instability (MSI).
• MSI can cause frameshift mutations in coding microsatellites, generating neoantigens.
• The O-linked N-acetylglucosamine transferase (OGT) gene harbors a T(10) microsatellite prone to frameshift mutations in MSI colorectal cancers.

Purpose of the Study:

• To identify and characterize a novel tumor-associated antigen derived from a frameshift mutation in the OGT gene.
• To investigate the potential of this neoantigen as a target for T-cell based cancer immunotherapy.

Main Methods:

• Identification of a frameshift mutation in the OGT gene's coding microsatellite in MSI colorectal cancers.
• Design and synthesis of a peptide (FSP06) derived from the mutant OGT protein.
• Generation and characterization of HLA-A0201-restricted cytotoxic T lymphocyte (CTL) clones specific for FSP06.
• Assessment of FSP06-specific CTL activity against peptide-sensitized target cells and tumor cell lines.

Main Results:

• A novel HLA-A0201-restricted CTL epitope (FSP06) was identified from the mutant OGT protein.
• FSP06-specific CTL clones demonstrated cytotoxic activity against target cells presenting the epitope.
• Endogenous expression of FSP06 was confirmed in tumor cells with deficient mismatch repair and HLA-A0201 expression.

Conclusions:

• Frameshift peptides, such as FSP06 derived from the OGT gene, represent a novel class of tumor-associated antigens.
• These antigens are specifically found in cancers with deficient mismatch repair.
• FSP06 serves as a CD8+ T cell epitope, validating frameshift peptides as potential targets for cancer immunotherapy in MSI-driven tumors.