Prostate-specific membrane antigen-derived peptide–Major Histocompatibility Complex (PSMA-pMHC)

Prostate-specific membrane antigen-derived peptide–Major Histocompatibility Complex (PSMA-pMHC) refers to the molecular assembly of a specific PSMA-derived epitope bound within the groove of an MHC class I molecule, typically HLA-A*02:01, on the cell surface (UniProt: Q04609). While PSMA itself is a transmembrane glycoprotein highly overexpressed in prostate cancer cells, the pMHC complex represents the specific ligand recognized by the T-cell receptors (TCRs) of cytotoxic T lymphocytes. This target is the foundation for TCR-engineered T-cell (TCR-T) therapies, which aim to redirect the immune system to recognize and eliminate malignant cells presenting these specific processed peptides (Poseida Therapeutics, 2023). Unlike traditional CAR-T therapies that bind to the extracellular domain of the whole protein, TCR-T therapies targeting PSMA-pMHC can recognize antigens derived from both surface and intracellular protein processing, potentially offering higher sensitivity. Clinical development of drugs targeting this complex, such as P-PSMA-TCR-I, focuses on treating metastatic castration-resistant prostate cancer (NCT04268420). Key challenges include the requirement for specific HLA-matching in patients and potential on-target, off-tumor toxicities in healthy tissues like the salivary glands and kidneys where PSMA is physiologically expressed.

Other names

PSMA-HLA complexPSMA peptide-MHC complexPSMA-derived pMHCFOLH1-peptide-MHCPSMA-HLA-A*02:01 complex

T-cell receptor (TCR) recognition of the specific PSMA peptide presented within the MHC groove triggers T-cell activation, leading to the release of perforins and granzymes that induce apoptosis in the target tumor cell (Hillerdal et al., 2014, PubMed: 24413455).