Wild-type Kirsten rat sarcoma virus proto-oncogene-derived peptide epitopes presented on Major Histocompatibility Complex (WT KRAS-MHC)

Wild-type KRAS-derived peptide epitopes presented on the Major Histocompatibility Complex (MHC) are short protein fragments derived from the normal KRAS protein and displayed on the cell surface (Source: Rock et al., Trends Immunol 2016). KRAS is a small GTPase that acts as a molecular switch in signaling pathways like RAS/MAPK, which are essential for cell growth and survival (Source: Simanshu et al., Cell 2017). These wild-type epitopes are presented by MHC Class I molecules and are recognized by the immune system to maintain self-tolerance. In the field of oncology, these complexes are not desirable therapeutic targets but are critical off-targets that must be avoided to prevent systemic toxicity (Source: Leidner et al., N Engl J Med 2022). Because wild-type KRAS is expressed in nearly all healthy tissues, any immunotherapy, such as TCR-T cells or bispecific antibodies, that cross-reacts with these epitopes would cause severe on-target, off-tumor damage (Source: Waters et al., Cold Spring Harb Perspect Med 2018). Consequently, these epitopes serve as vital negative controls in the development of mutant-specific KRAS therapies to ensure high precision and safety.

Other names

Wild-type KRAS-HLA complexWT KRAS peptide-MHCKRAS wild-type antigenWT KRAS-derived epitopes

Recognition by T-cell receptors (TCRs) or TCR-mimetic antibodies leading to T-cell mediated cytotoxicity (Source: Wang et al., J Exp Med 2016).