Tumor-specific frameshift peptide neoantigen (FSP neoantigen) (FSP neoantigen)

Tumor-specific frameshift peptide (FSP) neoantigens are novel protein sequences generated by insertion or deletion mutations in microsatellite regions, a hallmark of tumors with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H) (Mandal et al., 2019, Science). These mutations cause a shift in the translational reading frame, resulting in entirely new, highly immunogenic peptide sequences that the immune system perceives as foreign (Roudko et al., 2020, Lancet Oncology). Unlike many neoantigens that are unique to an individual, certain FSPs are frequently recurrent or shared across different patients with MSI-H cancers, such as colorectal, gastric, and endometrial malignancies (D'Alise et al., 2022, Science Translational Medicine). These peptides are processed and presented by MHC class I and II molecules, serving as potent targets for T-cell mediated destruction (Le et al., 2015, NEJM). Therapeutic approaches include viral-vectored or peptide-based vaccines, such as NOUS-209, which are designed to elicit broad CD8+ and CD4+ T-cell responses against a panel of shared FSPs (D'Alise et al., 2022, Science Translational Medicine). Because FSPs are absent in healthy tissues, they provide a high degree of tumor specificity, potentially minimizing the risk of off-target toxicity while overcoming resistance to checkpoint inhibitors (Balli et al., 2022, Journal for ImmunoTherapy of Cancer).

Other names

Frameshift-derived neoantigenMSI-H shared neoantigenShared frameshift peptideFSPMSI-derived neoantigen

Induction of a robust, polyfunctional CD8+ and CD4+ T-cell response against tumor cells presenting shared frameshift peptides on MHC molecules (D'Alise et al., 2022, Science Translational Medicine).