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

Tumor-associated antigen-derived peptide-Major Histocompatibility Complex (TAA-pMHC) complexes are molecular assemblies on the surface of cancer cells that present fragments of intracellular proteins to the immune system. These complexes consist of a peptide ligand, typically 8-11 amino acids for MHC Class I, nestled within the binding groove of a Major Histocompatibility Complex (MHC) molecule, known as Human Leukocyte Antigen (HLA) in humans (Savage et al., 2023). By presenting peptides derived from mutated (neoantigens), overexpressed, or lineage-specific proteins, pMHC complexes allow T-cells to detect internal cellular transformations that are otherwise invisible to traditional antibodies (Koneru et al., 2021). Therapeutic interventions such as TCR-engineered T-cells (TCR-T) and bispecific TCR-based engagers are engineered to recognize these complexes with high specificity to induce T-cell mediated lysis of the tumor (FDA, 2022). However, the clinical application of pMHC-targeting drugs is complicated by the requirement for specific HLA haplotypes in patients and the risk of lethal off-target cross-reactivity with similar peptides in healthy tissues (Linette et al., 2013). Furthermore, tumors may develop resistance through the loss of HLA expression or mutations in the antigen processing machinery (Savage et al., 2023).

Other names

pMHC complexPeptide-MHC complexHLA-peptide complexTumor-specific MHC-peptide complexNeoantigen-MHC complex

Engagement of the peptide-MHC complex by engineered T-cell receptors (TCRs) or TCR-mimetic antibodies to redirect T-cell cytotoxicity against tumor cells.