Melanoma tumor-associated antigen peptide–major histocompatibility complex (Melanoma pMHC)

Melanoma tumor-associated antigen peptide–major histocompatibility complex (pMHC) complexes are molecular assemblies on the surface of melanoma cells that present intracellularly derived peptides to the immune system (Koneru et al., 2015, Journal of Hematology & Oncology). These complexes are formed when fragments of proteins specifically expressed or overexpressed in melanoma—such as gp100, MART-1, MAGE-A4, or NY-ESO-1—are processed and loaded onto Major Histocompatibility Complex (MHC) Class I molecules, most commonly HLA-A*02:01 (Vigneron, 2015, Cancer Immunotherapy). The resulting pMHC complex acts as a specific ligand that can be recognized by the T-cell receptors (TCRs) of cytotoxic T lymphocytes, triggering an immune response (Holliday et al., 2023, Frontiers in Immunology). In oncology, these complexes are critical therapeutic targets because they allow for the targeting of intracellular proteins that cannot be reached by traditional antibody-based therapies (Saini et al., 2021, Science Immunology). Modern immunotherapies, such as TCR-engineered T-cells (TCR-T) like afamitresgene autoleucel and bispecific T-cell engagers like tebentafusp, are designed to bind these specific pMHC targets with high affinity to induce tumor cell lysis (Nathan et al., 2021, NEJM; D'Angelo et al., 2024, Lancet). However, therapeutic success is limited by the requirement for specific HLA haplotypes and the potential for tumor escape through HLA downregulation or loss of antigen expression (Jhunjhunwala et al., 2021, Nature Reviews Cancer).

Other names

Melanoma-associated antigen-MHC complexTumor-specific peptide-MHC complexpMHC complexHLA-peptide complexMelanoma tumor-associated antigen peptide–MHC complexes

Redirection of T-cell cytotoxicity via high-affinity binding of engineered T-cell receptors (TCRs) or bispecific engagers to specific peptide-MHC complexes on the tumor cell surface.