Mutant RAS peptide–Major Histocompatibility Complex (Mutant RAS-pMHC)

Mutant RAS peptide–Major Histocompatibility Complex (pMHC) complexes are cell-surface structures composed of a mutated RAS protein fragment (neoantigen) bound to a Major Histocompatibility Complex (MHC) molecule. RAS proteins, including KRAS, NRAS, and HRAS, are frequently mutated in human cancers, particularly in pancreatic, colorectal, and lung malignancies. Although RAS is an intracellular protein, its mutant forms are processed by the proteasome into short peptides that are subsequently presented on the cell surface by MHC Class I or II molecules for recognition by T-cells (Sim et al., 2020). These pMHC complexes serve as highly specific tumor markers because the mutant peptide sequence is absent in normal cells, providing a therapeutic window for immunotherapy (Wang et al., 2021). Current therapeutic approaches targeting these complexes include TCR-engineered T-cell (TCR-T) therapies, which utilize synthetic T-cell receptors to recognize specific RAS-pMHC combinations, and neoantigen vaccines like ELI-002 that prime the endogenous immune system (Leidner et al., 2022; Pant et al., 2023). The primary clinical challenge is the requirement for patient-specific HLA matching and the potential for tumor resistance through the loss of HLA expression or antigen processing machinery.

Other names

RAS neoantigen-HLA complexKRAS mutant pMHCMutant RAS-HLA complexRAS-derived neoepitope-MHC

T-cell receptor (TCR) mediated recognition and killing; Active immunization against neoepitopes; Redirection of T-cells via bispecific antibodies