Structural maintenance of chromosomes protein 1A (SMC1A) frameshift neoantigen–HLA complex (SMC1A FS–HLA)

Structural maintenance of chromosomes protein 1A (SMC1A) frameshift neoantigen–HLA complexes represent a class of highly specific tumor targets found in cancers characterized by microsatellite instability (MSI-H) or deficient mismatch repair (dMMR) (PMID: 31533962). In these tumors, replication errors in the SMC1A gene lead to frameshift mutations that generate a novel, non-self C-terminal peptide sequence (PMID: 28834741). This neoantigenic peptide is subsequently processed and presented on the cell surface by Major Histocompatibility Complex (MHC) class I molecules, most commonly HLA-A*02:01, where it can be recognized by the T-cell receptor (TCR) of cytotoxic T lymphocytes (PMID: 33073218). Unlike wild-type SMC1A, which is ubiquitously expressed and involved in chromosome cohesion, the frameshift-derived peptide is exclusively expressed by malignant cells, minimizing the risk of on-target, off-tumor toxicity (UniProt P17947). Therapeutic approaches targeting this complex include neoantigen-based vaccines, such as NOUS-209, and the development of adoptive cell therapies using TCR-engineered T cells (Nouscom, 2024). These strategies aim to leverage the high immunogenicity of shared frameshift neoantigens to treat MSI-H colorectal, gastric, and endometrial carcinomas.

Other names

SMC1A frameshift peptide-HLA complexSMC1A neoantigenSMC1A-FSSMC1A frameshift-derived neoantigenSMC1A-FS/HLA-A*02:01

T-cell mediated cytotoxicity via TCR recognition of the peptide-HLA complex