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

Tumor-associated antigen peptide–Major Histocompatibility Complex (TAA-pMHC) refers to the presentation of intracellular tumor-derived protein fragments on the cell surface by MHC molecules (HLA in humans). This biological process is essential for the adaptive immune system to monitor the internal proteome for mutations or abnormal protein expression (Nature Reviews Cancer, 2021). In oncology, these complexes serve as highly specific targets for immunotherapies, such as TCR-engineered T-cells (TCR-T) and bispecific TCR-based fusion proteins, which can distinguish cancer cells from healthy ones by recognizing specific peptide-HLA combinations (Nature Reviews Drug Discovery, 2023). Unlike traditional antibody targets that must be surface-expressed proteins, TAA-pMHC targeting allows access to the vast majority of the proteome that is intracellular. Notable therapeutic examples include Tebentafusp for gp100-positive melanoma and Afamitresgene autoleucel for MAGE-A4-positive synovial sarcoma (NEJM, 2022; FDA, 2024). However, the clinical application of these therapies is limited by the high degree of HLA polymorphism and the risk of lethal cross-reactivity with similar peptides in vital organs (Journal for ImmunoTherapy of Cancer, 2021).

Other names

Tumor-specific antigen-MHC complexHLA-peptide complexNeoantigen-MHC complexCancer-germline antigen-MHC complexpMHC

Drugs targeting TAA-pMHC complexes utilize engineered T-cell receptors (TCRs) or TCR-mimetic antibodies to recognize specific peptide fragments presented by HLA molecules, triggering T-cell mediated cytotoxicity against the tumor cell.