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

Tumor-associated antigen–derived peptide–Major Histocompatibility Complex (TAA-pMHC) complexes are molecular assemblies consisting of a short peptide fragment (typically 8–15 amino acids) derived from an intracellular tumor protein bound within the groove of a Major Histocompatibility Complex (MHC) molecule (Nature Reviews Immunology, 2019). These complexes are displayed on the surface of tumor cells and professional antigen-presenting cells, serving as the primary ligand for T-cell recognition via the T-cell receptor (TCR) (PubMed: 30242282). In oncology, TAA-pMHCs are highly valued therapeutic targets because they allow the immune system to detect intracellular mutations, fetal antigens, or overexpressed proteins that are not accessible to traditional monoclonal antibodies (Science, 2021). Current therapeutic strategies targeting these complexes include TCR-engineered T-cells (TCR-T) and TCR-bispecific engagers like Tebentafusp, which specifically targets the gp100 peptide presented by HLA-A*02:01 (NEJM, 2021). However, clinical development is complicated by the requirement for specific patient HLA haplotypes and the significant risk of lethal off-target cross-reactivity if the targeted peptide sequence shares homology with proteins expressed in vital organs (Journal for ImmunoTherapy of Cancer, 2020).

Other names

Tumor-associated antigen-peptide-MHC complexpMHCHLA-peptide complexNeoantigen-MHC complexPeptide-HLA complex

Therapeutic agents target TAA-pMHC complexes through engineered T-cell receptors (TCRs) or TCR-mimetic antibodies that recognize the specific spatial configuration of a tumor-derived peptide nestled within the MHC groove, triggering T-cell mediated lysis of the target cell.