Mutant Kirsten rat sarcoma virus oncogene homolog (KRAS) peptide-Major Histocompatibility Complex (MHC) complex (Mutant KRAS-MHC)

The mutant Kirsten rat sarcoma virus oncogene homolog (KRAS) peptide-Major Histocompatibility Complex (MHC) complex is a highly specific tumor neoantigen target used in cancer immunotherapy. KRAS is a GTPase that normally regulates cell signaling, but mutations—most frequently at codons 12, 13, or 61—lead to constitutive activation and drive the progression of pancreatic, colorectal, and lung cancers (UniProt P01116). These intracellular mutant proteins are processed by the proteasome into short peptides and presented on the cell surface by MHC molecules, allowing the immune system to distinguish malignant cells from healthy ones (PubMed: 35648468). Because these specific peptide sequences are absent in normal tissue, they serve as ideal targets for T-cell receptor (TCR) based therapies and neoantigen vaccines (NEJM: 386:2112-2119). Therapeutic strategies include TCR-engineered T-cell (TCR-T) therapies, which provide patients with T cells specifically primed to recognize these complexes, and peptide or mRNA vaccines designed to elicit an endogenous immune response (Nature Medicine: 30, 413–423). The efficacy of these treatments is highly dependent on the patient's specific HLA genotype and the presence of the corresponding KRAS mutation. While promising, challenges include the potential for tumor escape through MHC downregulation and the logistical complexity of matching TCRs to specific HLA-peptide combinations.

Other names

KRAS neoantigenMutant KRAS peptide-HLA complexKRAS G12D/G12V/G12C neoantigenmKRAS-MHCKRAS-derived peptide-MHC complex

Recognition of the specific mutant KRAS peptide-MHC complex by endogenous or engineered T-cell receptors (TCRs), which triggers a cytotoxic immune response and targeted lysis of the tumor cell.