Tumor antigen-derived peptide-Major Histocompatibility Complex (pMHC)

Tumor antigen-derived peptide–Major Histocompatibility Complex (pMHC) complexes are the primary targets for T-cell-mediated immunity, representing fragments of intracellular proteins displayed on the cell surface (PMID: 31515431). These complexes are formed when cellular proteins are degraded by the proteasome into short peptides, which are then loaded onto MHC Class I or II molecules and transported to the plasma membrane (PMID: 29305541). In cancer, these peptides can be derived from mutated proteins (neoantigens), overexpressed proteins (tumor-associated antigens), or cancer-germline antigens like MAGE-A4 or NY-ESO-1 (PMID: 34161772). Therapeutic strategies targeting pMHC complexes include TCR-engineered T cells (TCR-T) and TCR-bispecific molecules, such as Tebentafusp, which redirect the immune system to recognize specific peptide-HLA combinations (FDA, 2022). Because pMHC complexes provide a window into the internal proteome, they allow for the targeting of proteins that are otherwise inaccessible to traditional monoclonal antibodies. However, the high specificity required to distinguish tumor pMHC from similar self-peptides on healthy tissue presents a significant safety challenge, often leading to risks of off-target toxicity (PMID: 23943301).

Other names

pHLAPeptide-HLA complexMHC-restricted tumor antigenTumor-specific peptide-MHCNeoantigen-MHC complexMHC-peptide complex

T-cell receptor (TCR) binding and activation, Bispecific T-cell engagement (TCR-CD3), Adoptive T-cell transfer (TCR-T), TCR-like antibody-mediated cytotoxicity