T-cell receptor recognizing MHC–frameshift neoantigen complexes (TCR-fsNeo)

T-cell receptors (TCRs) recognizing MHC–frameshift neoantigen complexes are specialized immune receptors designed to identify and bind to novel peptide sequences resulting from frameshift mutations in tumor cells. These mutations, which are particularly prevalent in cancers characterized by microsatellite instability (MSI) or mismatch repair deficiency (dMMR), create "non-self" proteins that are highly immunogenic and absent from normal tissues (Le et al., Science, 2017). Because certain frameshift mutations occur recurrently across different patients, these TCRs are being developed as potent "off-the-shelf" TCR-T cell therapies (Roudko et al., Cancer Cell, 2020). Upon binding to the specific neoantigen presented by Major Histocompatibility Complex (MHC) molecules, the TCR initiates a signaling cascade that activates the T-cell's cytotoxic machinery, including the release of perforins and granzymes to induce tumor cell apoptosis. This therapeutic strategy offers high specificity and a favorable safety profile due to the lack of expression of these frameshifted sequences in healthy cells (Mandal et al., Nature, 2019). Furthermore, targeting shared frameshift neoantigens overcomes the logistical challenges of personalized neoantigen therapy, providing a more scalable approach for treating MSI-H colorectal, gastric, and endometrial cancers.

Other names

Frameshift-specific T-cell receptorMSI-neoantigen TCRNeoantigen-reactive T-cell receptorShared frameshift-specific TCRTCR recognizing shared frameshift neoantigens

Specific binding to neoantigen-MHC complexes on tumor cells, triggering T-cell receptor signaling and subsequent granzyme/perforin-mediated apoptosis of the target cell.