Frameshift-derived neopeptide (FSP)

Frameshift-derived neopeptides (FSPs) are a unique class of neoantigens resulting from insertions or deletions in coding microsatellites, a hallmark of mismatch repair-deficient (dMMR) and microsatellite instability-high (MSI-H) cancers (Kloor & von Knebel Doeberitz, Trends Cancer, 2016). These mutations shift the reading frame of the mRNA, leading to the translation of novel, non-self peptide sequences that are highly immunogenic because they have not been filtered by central immune tolerance (Roudko et al., Front Oncol, 2021). In therapeutic applications, these neopeptides are often pooled and presented by autologous dendritic cells to prime the patient's immune system, specifically targeting the HLA class I and II pathways to elicit both CD8+ and CD4+ T-cell responses (Schwitalle et al., Gastroenterology, 2008). This approach is particularly promising for Lynch syndrome patients and those with sporadic MSI-H tumors, such as colorectal and endometrial carcinomas (ClinicalTrials.gov, NCT01885702). By targeting shared or personalized FSPs, these vaccines aim to overcome the immunosuppressive tumor microenvironment and provide a targeted, durable anti-tumor response. The use of autologous dendritic cells ensures that the neopeptides are presented in a highly stimulatory context, maximizing the likelihood of generating effective memory T cells. Clinical development of these targets includes both off-the-shelf vaccines targeting common shared mutations and personalized approaches tailored to an individual's tumor profile.

Other names

Frameshift peptidesMSI-derived neopeptidesMismatch repair-deficient neopeptidesFrameshift-derived neoantigensFSPs

Induction of tumor-specific T-cell responses (CD4+ and CD8+) against frameshift-derived neoantigens presented on the surface of tumor cells.