KRAS G12D mutant peptide presented by HLA-C*08:02 (KRAS G12D/HLA-C*08:02)

The KRAS G12D mutant peptide presented by HLA-C*08:02 is a tumor-specific neoantigen complex that serves as a critical target for personalized immunotherapy. KRAS is a member of the RAS family of GTPases involved in cell signaling; the G12D mutation is a frequent driver in pancreatic, colorectal, and lung cancers (Simanshu et al., Cell, 2017). When this mutated protein is degraded by the proteasome, the resulting peptide (typically the 9-mer GADGVGKSA) is presented on the cell surface by the specific Class I Major Histocompatibility Complex (MHC) allele HLA-C*08:02 (Tran et al., N Engl J Med, 2016). This complex is absent in normal cells, making it an ideal target for T-cell receptor (TCR) based therapies, which can distinguish the mutant peptide from the wild-type KRAS sequence. Therapeutic interventions, such as TCR-engineered T-cell therapy (TCR-T), utilize synthetic or patient-derived TCRs to recognize this complex and trigger a cytotoxic immune response against the tumor (Leidner et al., N Engl J Med, 2022). The clinical utility of this target is restricted to patients who both harbor the KRAS G12D mutation and express the HLA-C*08:02 allele, representing a paradigm of precision oncology.

Other names

KRAS G12D neoantigenKRAS G12D-HLA-C*08:02 complexG12D-HLA-C*08:02KRAS G12D/MHC class I complex

The mechanism involves the specific recognition of the KRAS G12D mutant peptide bound to the HLA-C*08:02 molecule by the T-cell receptor (TCR) of an engineered T cell. This binding event triggers the formation of an immunological synapse, leading to the release of cytotoxic molecules like perforin and granzymes, which induce apoptosis in the tumor cell (Tran et al., N Engl J Med, 2016; Leidner et al., N Engl J Med, 2022).