Tumor-specific frameshift neoantigen (FSNA)

Tumor-specific frameshift neoantigens (FSNAs) are novel peptides generated by insertion or deletion (indel) mutations that shift the open reading frame of a gene, resulting in a completely new amino acid sequence downstream of the mutation (Mandal et al., 2019, Nature). These peptides are processed by the proteasome and presented by Major Histocompatibility Complex (MHC) class I molecules on the surface of tumor cells, where they are recognized as foreign by the host's immune system (Turajlic et al., 2017, Lancet Oncology). Because FSNAs are entirely absent from the normal human proteome, they possess high immunogenicity and are less likely to be subject to central immune tolerance compared to single nucleotide variants (SNVs). They are particularly prevalent in cancers with microsatellite instability (MSI) or deficient mismatch repair (dMMR), such as Lynch syndrome-associated colorectal and endometrial cancers (D'Alise et al., 2022, Science Translational Medicine). Therapeutic strategies targeting these neoantigens include personalized or off-the-shelf cancer vaccines and TCR-engineered T-cell therapies designed to elicit a robust, targeted cytotoxic T-cell response against the tumor. Clinical development of agents like Nous-209 leverages shared frameshift mutations found across multiple patients to create standardized immunotherapies for MSI-H malignancies (Nouscom, 2024).

Other names

Frameshift-derived neoantigenFrameshift peptide (FSP)Microsatellite instability-derived neoantigenIndel-derived neoantigenNeoantigenic frameshift peptide

Induction of tumor-specific CD8+ cytotoxic T-cell and CD4+ helper T-cell responses through vaccination (DNA, RNA, or peptide) or adoptive transfer of TCR-engineered T cells that recognize the frameshift peptide-MHC complex.