BRAF V600E-derived peptide–Major Histocompatibility Complex (MHC) (BRAF V600E-pMHC)

The BRAF V600E-derived peptide–MHC complex is a tumor-specific neoantigen formed when the mutated BRAF V600E protein is processed by the cellular machinery and its resulting peptides are presented on the cell surface by Major Histocompatibility Complex (MHC) molecules (Veatch et al., 2018). This complex is a significant therapeutic target because the V600E mutation is a driver mutation found in approximately 50% of melanomas and various other cancers, but is absent in normal tissues (UniProt P15056). Immunotherapies such as T-cell receptor (TCR) engineered T cells and TCR-mimic antibodies are designed to recognize this specific peptide-MHC combination, allowing for the selective destruction of malignant cells. Unlike small-molecule inhibitors that target the BRAF kinase activity, targeting the pMHC complex utilizes the immune system's specificity to overcome drug resistance. The clinical utility of this target is dependent on the patient's HLA profile, as the peptide must be presented by a specific MHC allele (e.g., HLA-A*02:01) to be recognized by the therapeutic agent. Research has shown that T cells recognizing this neoantigen can be found in patients, suggesting it is a naturally occurring and viable target for immunotherapy (PubMed: 29433553). Therapeutic development focuses on creating high-affinity TCRs that can distinguish the single amino acid substitution of the V600E mutation from the wild-type sequence. This target represents a personalized medicine approach, combining genetic profiling of the tumor with HLA typing of the patient.

Other names

BRAF V600E neoantigenBRAF V600E-HLA complexBRAF V600E-MHC class I complexBRAF V600E-HLA-A*02:01 complex

T-cell receptor (TCR) binding to the peptide-MHC complex leading to T-cell activation and tumor cell lysis.