T cell receptor specific for SMC1A frameshift peptide–HLA complex (TCR-SMC1A-FS)

T cell receptors (TCRs) specific for SMC1A frameshift (FS) peptide–HLA complexes are specialized immune receptors designed to recognize a specific neoantigen generated by frameshift mutations in the Structural Maintenance of Chromosomes 1A (SMC1A) gene. These mutations are highly recurrent in cancers characterized by microsatellite instability (MSI), such as colorectal, gastric, and endometrial carcinomas (Mandal et al., 2019, Cancer Discovery). Because the frameshift creates a novel C-terminal protein sequence not present in healthy cells, it serves as a highly tumor-specific target for immunotherapy (Roudko et al., 2020, Cancer Cell). Therapeutic strategies involve engineering T cells to express these specific TCRs (TCR-T therapy) to selectively identify and eliminate malignant cells presenting the SMC1A-FS peptide on their HLA molecules, most commonly HLA-A*02:01. This approach aims to provide a precision medicine solution for MSI-H patients who may not respond sufficiently to standard checkpoint inhibitors. The high specificity of the TCR for the neoantigen-HLA complex minimizes the risk of attacking normal tissues, although potential cross-reactivity remains a critical safety consideration. As a shared neoantigen, SMC1A-FS allows for the development of off-the-shelf TCR-T products suitable for a subset of patients sharing the same HLA type.

Other names

SMC1A neoantigen-specific T-cell receptorTCR targeting SMC1A frameshift mutationSMC1A-FS-HLA-A2 specific TCRSMC1A frameshift-specific T-cell receptor

Engineered or endogenous T-cell receptors recognize the specific frameshift-derived neoepitope of SMC1A presented by HLA molecules on the surface of tumor cells, triggering cytotoxic T-lymphocyte mediated destruction of the cancer cell.