Mutant Kirsten rat sarcoma virus oncogene homolog (KRAS) peptides presented by Human Leukocyte Antigen (HLA) class I (Mutant KRAS-HLA-I complex)

Mutant KRAS peptides presented by HLA class I represent a class of tumor-specific neoantigens that are highly sought after in cancer immunotherapy (Tran et al., 2016, N Engl J Med). KRAS is one of the most frequently mutated oncogenes in human cancers, particularly in pancreatic, colorectal, and lung adenocarcinomas (Simanshu et al., 2017, Cell). When KRAS undergoes somatic mutations, such as G12D, G12V, or G12C, the resulting mutant proteins are processed by the proteasome into short peptides. These peptides are then loaded onto Human Leukocyte Antigen (HLA) class I molecules and transported to the cell surface (Bear et al., 2022, Nat Commun). These peptide-HLA complexes serve as unique flags that can be recognized by the T-cell receptors (TCRs) of cytotoxic T lymphocytes. Because these mutant sequences are absent in healthy tissues, they provide an ideal target for highly specific therapies, including TCR-engineered T-cell (TCR-T) therapies and cancer vaccines. Examples of such therapies include the peptide vaccine ELI-002 and the mRNA-based vaccine mRNA-5671 (Elicio Therapeutics; Moderna). Targeting these complexes aims to bypass the historically undruggable nature of the KRAS protein itself by leveraging the immune system to eliminate cells expressing the intracellular mutation. This approach is particularly valuable for patients with specific HLA genotypes that can effectively present these mutant epitopes (Wang et al., 2021, Front Immunol).

Other names

KRAS neoantigen-HLA complexMutant KRAS-MHC class I complexKRAS G12D-HLA complexKRAS G12V-HLA complexKRAS G12C-HLA complexKRAS neoepitope

T-cell receptor (TCR) mediated recognition of the peptide-HLA complex leading to cytotoxic T-lymphocyte (CTL) activation and tumor cell lysis.