Melanoma-associated peptide-major histocompatibility complex (Melanoma pMHC)

Melanoma-associated peptide-major histocompatibility complexes (pMHCs) are cell-surface structures composed of a tumor-derived peptide fragment bound to a Human Leukocyte Antigen (HLA) molecule (Janeway's Immunobiology, 9th ed.). These complexes serve as the primary signal for the adaptive immune system to recognize and eliminate malignant cells, as they display fragments of intracellular proteins that would otherwise be invisible to traditional antibody-based therapies. In melanoma, common peptides presented include those derived from lineage-specific proteins like gp100 or cancer-testis antigens such as MAGE-A4 and NY-ESO-1 (D'Angelo et al., Lancet Oncology 2023). Modern immunotherapies, such as ImmTACs (Immune mobilizing monoclonal TCRs against cancer) and TCR-engineered T-cells, are designed to bind these specific pMHCs with high affinity to trigger a potent cytotoxic T-cell response. Because these targets are HLA-restricted, clinical application is currently limited to patients carrying specific HLA alleles, most commonly HLA-A*02:01 (Nathan et al., NEJM 2021).

Other names

Melanoma-associated HLA-peptide complexTumor-specific peptide-MHCpMHCHLA-presented melanoma antigensMelanoma-associated HLA-presented peptide–MHC complexes

Targeting of specific peptide-HLA complexes via engineered T-cell receptors (TCRs) or TCR-based bispecific molecules to induce T-cell mediated lysis of tumor cells (Nathan et al., NEJM 2021).