Mutant Kirsten rat sarcoma virus oncogene homolog-derived peptides presented by Major Histocompatibility Complex (Mutant KRAS-MHC)

Mutant Kirsten rat sarcoma virus oncogene homolog (KRAS)-derived peptides presented by the Major Histocompatibility Complex (MHC) are a class of tumor-specific neoantigens essential for immune-mediated cancer surveillance. KRAS is a small GTPase that frequently undergoes somatic mutations at codons 12, 13, or 61, which are prevalent in pancreatic, colorectal, and lung adenocarcinomas (Wang et al., 2021). These intracellular mutant proteins are degraded into short peptide fragments and loaded onto MHC Class I molecules for presentation on the cell surface (Simanshu et al., 2017). This complex serves as a unique molecular signature that can be recognized by the T-cell receptors (TCRs) of cytotoxic T lymphocytes, distinguishing malignant cells from normal tissue (Tran et al., 2016). Therapeutic strategies targeting these complexes include TCR-engineered T-cell (TCR-T) therapies, which provide patients with T cells expressing high-affinity receptors for specific KRAS-MHC combinations, and neoantigen vaccines like ELI-002 that aim to expand endogenous T-cell populations (Pant et al., 2024). A significant challenge in this field is the requirement for specific HLA matching, as a given KRAS peptide must be presented by a compatible HLA allele (e.g., HLA-C*08:02 or HLA-A*11:01) to be recognized (Bear et al., 2021). Additionally, tumors may escape treatment through the downregulation of MHC expression or other components of the antigen-processing machinery.

Other names

KRAS neoantigenMutant KRAS-HLA complexKRAS peptide-MHC complexKRAS pMHCMutant KRAS-derived neoepitopes

T-cell receptor (TCR) mediated recognition of the specific mutant peptide-MHC complex on the tumor cell surface, leading to the activation of cytotoxic T lymphocytes and subsequent immune-mediated tumor cell lysis.