Mutant Kirsten rat sarcoma virus oncogene homolog-derived peptide presented on Human Leukocyte Antigen class I (Mutant KRAS-HLA-I) (Mutant KRAS-HLA-I)

The mutant Kirsten rat sarcoma virus oncogene homolog (KRAS)-derived peptide presented on Human Leukocyte Antigen (HLA) class I is a tumor-specific neoantigen complex that serves as a critical target for cancer immunotherapy (Prior et al., 2020). KRAS is one of the most frequently mutated oncogenes in human cancers, particularly in pancreatic, colorectal, and non-small cell lung cancers (Simanshu et al., 2017). When KRAS undergoes specific mutations, such as G12D, G12V, or G12C, the resulting mutant proteins are processed into short peptides and presented on the cell surface by HLA class I molecules (Tran et al., 2016). These peptide-HLA (pHLA) complexes are uniquely present on malignant cells, making them ideal targets for T-cell-based therapies like TCR-engineered T-cells (TCR-T) and neoantigen vaccines (Affini-T Therapeutics, 2024). Therapeutic strategies aim to exploit the high specificity of these complexes to induce T-cell mediated cytotoxicity while sparing healthy tissues that express only wild-type KRAS (Elicio Therapeutics, 2024). However, challenges such as HLA downregulation and the requirement for specific HLA-allele matching in patients remain significant hurdles in the clinical application of these therapies (Tran et al., 2016).

Other names

KRAS neoantigen-HLA complexMutant KRAS peptide-MHC class I complexKRAS G12D-HLA-C*08:02 complexKRAS G12V-HLA-A*11:01 complexKRAS G12C-HLA-A*03:01 complex

Recognition of the mutant peptide-HLA complex by endogenous or engineered T-cell receptors (TCRs), leading to T-cell activation, secretion of cytotoxic granules (perforin/granzyme), and selective apoptosis of the tumor cell (Tran et al., 2016; Affini-T Therapeutics, 2024).