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

Tumor-associated antigen-derived peptide–Major Histocompatibility Complex (TAA-pMHC) refers to the presentation of intracellular tumor-derived peptides on the cell surface by MHC (or HLA in humans) molecules. This biological mechanism allows the immune system to monitor the internal protein composition of a cell, identifying malignant transformations through the presence of mutated, overexpressed, or aberrantly expressed proteins (Nature Reviews Drug Discovery, 2021). In oncology, TAA-pMHC complexes serve as highly specific targets for immunotherapies, particularly for antigens that are not expressed on the cell surface in their native form. Therapeutic interventions include TCR-engineered T-cells (TCR-T) and bispecific T-cell engagers (ImmTACs) designed to bind the specific peptide-HLA interface with high affinity (Frontiers in Immunology, 2020). Unlike traditional CAR-T therapies that target surface proteins, TAA-pMHC targeting expands the range of druggable targets to include the entire intracellular proteome. However, the efficacy of these therapies is strictly dependent on the patient's HLA genotype and the density of the target complex on the tumor surface (Journal of Hematology & Oncology, 2023). Clinical success has been demonstrated by agents like Tebentafusp, which targets a gp100 peptide-MHC complex in uveal melanoma.

Other names

Tumor-specific peptide-MHC complexHLA-peptide complexNeoantigen-MHC complexCancer-testis antigen-MHC complexpMHCPeptide-HLA complex

Therapeutic agents target TAA-pMHC complexes through engineered T-cell receptors (TCRs) or TCR-mimetic antibodies that recognize the specific interface of the peptide and the HLA groove, leading to T-cell activation and directed lysis of the tumor cell.