Tumor-associated antigen-Major Histocompatibility Complex complex (TAA-MHC) (pMHC)

The Tumor-associated antigen-Major Histocompatibility Complex (TAA-MHC) complex is a molecular assembly consisting of a short peptide fragment derived from an intracellular tumor protein bound to a Major Histocompatibility Complex (MHC) molecule on the cell surface [Nature Reviews Immunology, 2019]. This complex serves as the specific ligand for T-cell receptors (TCRs), enabling the immune system to monitor the internal health of a cell and identify malignant transformations [PubMed: 31263271]. In therapeutic contexts, these complexes are targeted by TCR-engineered T-cells (TCR-T) and bispecific T-cell engagers to direct a potent immune response against cancer cells [FDA: Kimmtrak, 2022]. Unlike traditional monoclonal antibodies that target surface proteins, TAA-MHC targeting allows access to the vast majority of the proteome that is located inside the cell, including oncogenic drivers like MAGE-A4 or NY-ESO-1 [FDA: Tecelra, 2024]. However, the efficacy of these therapies is restricted by the patient's HLA type and the risk of off-target toxicity if the target peptide is also presented by healthy tissues [Journal of Clinical Oncology, 2015]. Clinical challenges also include immune evasion through the downregulation of MHC molecules or the loss of the specific antigen by the tumor [Nature, 2017].

Other names

Peptide-Major Histocompatibility Complex complexpMHC complexpHLA complexTumor-associated antigen-MHC complexNeoantigen-MHC complex

Recognition by T-cell receptors (TCRs) or TCR-mimetic molecules, leading to T-cell mediated lysis of the target cell.