Mutant RAS protein-derived epitopes presented by Major Histocompatibility Complex (Mutant RAS-MHC)

Mutant RAS protein-derived epitopes presented by the Major Histocompatibility Complex (MHC) are a class of tumor-specific neoantigens that arise from somatic mutations in the KRAS, NRAS, or HRAS genes. These mutations, which are highly prevalent in pancreatic, colorectal, and lung cancers, result in the production of altered proteins that are processed into short peptides and displayed on the cell surface by MHC molecules (Simanshu et al., 2017, Cell). Because these mutant sequences are absent in healthy tissues, the resulting peptide-MHC (pMHC) complexes serve as highly specific targets for immunotherapy, allowing the immune system to distinguish malignant cells from normal ones (Tran et al., 2016, Science). Therapeutic strategies currently in development include TCR-engineered T-cell therapies (TCR-T), which utilize synthetic receptors to bind specific RAS-pMHC complexes, and neoantigen vaccines designed to stimulate a patient's endogenous T-cell response (Leidner et al., 2022, NEJM). The efficacy of these treatments is often restricted by the patient's specific HLA allele, as the mutant peptide must fit precisely within the MHC binding groove to be recognized (Pant et al., 2024, Nature Medicine). Targeting these epitopes represents a major frontier in precision oncology, offering the potential for potent anti-tumor activity with minimal off-target effects.

Other names

RAS neoantigensMutant RAS-HLA complexKRAS-derived peptide-MHCRAS-pMHCMutant RAS antigen

Therapeutic agents, such as TCR-engineered T-cells or vaccines, specifically recognize the mutant RAS peptide sequence bound within the MHC cleft, leading to the selective destruction of tumor cells by the immune system.