Kirsten rat sarcoma virus oncogene homolog (KRAS) mutant peptide-Human Leukocyte Antigen (HLA) class I complex (KRAS-HLA-I complex)

The Kirsten rat sarcoma virus oncogene homolog (KRAS) mutant peptide-Human Leukocyte Antigen (HLA) class I complex is a specific neoantigen target formed when mutated KRAS proteins are processed and presented on the surface of cancer cells. KRAS is a GTPase that plays a pivotal role in cell signaling; however, mutations at codons 12, 13, or 61 lead to constitutive activation and drive various malignancies, including pancreatic, colorectal, and lung cancers [PMID: 31578448]. These intracellular mutant proteins are degraded by the proteasome into short peptides, which are then loaded onto HLA class I molecules and transported to the plasma membrane [PMID: 27929009]. This complex serves as a highly specific "flag" for the immune system, as the mutant sequence is not present in healthy tissues. Therapeutic strategies targeting this complex include T-cell receptor-engineered T-cell (TCR-T) therapies, bispecific T-cell engagers (BiTEs), and peptide or mRNA vaccines designed to elicit a cytotoxic T-lymphocyte response [PMID: 35653311, PMID: 33649083]. While highly promising for its specificity, the effectiveness of targeting the KRAS-HLA complex can be limited by tumor-mediated HLA downregulation or the loss of heterozygosity at the HLA locus, which allows cells to escape immune detection [PMID: 32694154].

Other names

KRAS neoantigenMutant KRAS peptide-MHC complexKRAS-HLA complexpMHC complexKRAS G12D/G12V/G12C-HLA complex

Recognition of the mutant peptide-HLA complex by engineered T-cell receptors (TCRs) or TCR-like antibodies, triggering cytotoxic T-lymphocyte activation and selective lysis of tumor cells.