Peptide-Major Histocompatibility Complex presenting tumor-associated antigens (pMHC-TAA)

Peptide-Major Histocompatibility Complex (pMHC) complexes presenting tumor-associated antigens (TAAs) are essential molecular targets on the surface of cancer cells that facilitate immune recognition of intracellular proteins [Nature Reviews Cancer, 2020]. These complexes are formed when intracellular proteins are degraded by the proteasome into short peptides, which are then loaded onto MHC class I or II molecules and transported to the cell membrane [PubMed, 2019]. In oncology, these complexes present fragments of mutated, overexpressed, or lineage-specific proteins, such as NY-ESO-1 or MAGE-A4, making them visible to T-cell receptors (TCRs) [Science, 2021]. Therapeutic strategies targeting pMHCs include TCR-engineered T-cell therapies (TCR-T), bispecific TCR molecules like Tebentafusp, and peptide vaccines, which aim to induce or enhance a cytotoxic T-cell response against the tumor [FDA, 2022]. Unlike traditional monoclonal antibodies that target whole surface proteins, pMHC-targeting agents can address the vast majority of the proteome that resides inside the cell [Cell, 2018]. However, the clinical application of these therapies requires precise HLA matching of patients and carries risks of off-target toxicity if the target peptide sequence is shared by proteins in healthy tissues [Journal of Experimental Medicine, 2013].

Other names

pMHCHLA-peptide complexMHC-peptide complexTumor-specific pMHCAntigen-MHC complexpMHC-antigen complex

Recognition of specific peptide-MHC complexes by engineered T-cell receptors (TCRs), TCR-bispecific engagers, or TCR-mimetic antibodies to trigger T-cell mediated cytotoxicity and lysis of tumor cells [Nature Reviews Drug Discovery, 2021].