Frameshift neoantigen (FS neoantigen) (FS neoantigen)

Frameshift neoantigens are highly immunogenic, tumor-specific peptides resulting from insertions or deletions (indels) in the genome that shift the open reading frame of a gene (Turajlic et al., 2017, Lancet Oncology). These mutations create entirely novel amino acid sequences that the immune system perceives as foreign, as they are not present in the normal human proteome and thus bypass central tolerance (Mandal et al., 2019, Nature). They are particularly abundant in tumors characterized by microsatellite instability (MSI) or mismatch repair deficiency (dMMR), such as certain colorectal and endometrial cancers (Le et al., 2015, NEJM). Because these antigens are absent in healthy tissues, they represent high-quality targets for immunotherapy with a low risk of cross-reactivity (Schrock et al., 2019, JAMA Oncology). Current therapeutic approaches include personalized and "off-the-shelf" cancer vaccines, such as Nous-209, as well as TCR-engineered T-cell therapies designed to elicit a robust cytotoxic T-cell response against cells presenting these neoantigens (D'Alise et al., 2022, Science Translational Medicine). These therapies aim to leverage the high immunogenicity of frameshift peptides to overcome the immunosuppressive tumor microenvironment and provide durable clinical responses (Gritstone bio, 2024).

Other names

Frameshift-derived neoantigenFrameshift peptideFSPIndel-derived neoantigenNeo-ORF peptide

Induction of a de novo, tumor-specific cytotoxic T-lymphocyte (CTL) response against novel, non-self peptide sequences presented on MHC molecules following frameshift mutations (Turajlic et al., 2017).