Tumor antigen peptide–Major Histocompatibility Complex (pMHC)

Tumor antigen peptide–Major Histocompatibility Complex (pMHC) complexes are molecular assemblies consisting of a short peptide derived from a tumor-specific or tumor-associated protein bound to an MHC molecule on the cell surface (PMID: 29942086). These complexes serve as the primary ligands for T-cell receptors (TCRs), enabling the immune system to recognize and eliminate malignant cells based on their internal proteome (PMID: 31048553). In therapeutic development, pMHCs are targeted by TCR-engineered T-cells and bispecific molecules, such as Tebentafusp, which redirects T-cells to kill gp100-expressing melanoma cells (PMID: 34551229). Unlike traditional CAR-T targets which must be surface proteins, pMHC targeting allows access to the vast majority of the proteome that is intracellular (PMID: 28803735). However, challenges include the requirement for specific HLA alleles in patients and the risk of off-target toxicity if the target peptide is mimicked by healthy tissue proteins (PMID: 23846750).

Other names

Tumor-associated antigen-MHC complexHLA-peptide complexNeoantigen-MHC complexpMHC complexAntigen-MHC complexPeptide-HLA complex

Therapeutic agents, such as TCR-engineered T-cells or bispecific T-cell engagers, bind specifically to the peptide-MHC complex on the tumor cell surface, facilitating the formation of an immunological synapse and subsequent T-cell mediated cytotoxicity (PMID: 34551229).