Tumor-associated antigen–Major Histocompatibility Complex (TAA-MHC) (TAA-MHC)

The Tumor-associated antigen–Major Histocompatibility Complex (TAA-MHC) is a molecular assembly consisting of a short peptide fragment derived from a tumor-specific or tumor-associated protein bound within the groove of an MHC (or HLA in humans) molecule. This complex is displayed on the surface of malignant cells and serves as the fundamental unit for recognition by the T-cell receptor (TCR) of CD4+ and CD8+ T lymphocytes (Nature Reviews Drug Discovery, 2021; PMID: 33536591). In the context of immunotherapy, this complex is a critical therapeutic target for TCR-engineered T-cell (TCR-T) therapies and bispecific T-cell engagers, such as Tebentafusp, which are designed to bypass natural immune tolerance (New England Journal of Medicine, 2021; PMID: 34551229). By targeting intracellular proteins that are processed and presented as pMHC, these therapies can address a much broader range of targets than traditional antibody-based therapies, which are limited to surface-expressed proteins (Frontiers in Immunology, 2020; PMID: 32117311). However, the efficacy of targeting TAA-MHC is highly dependent on the patient's specific HLA haplotype and the density of the antigen presentation on the tumor surface. Safety concerns include off-target toxicity if the targeted peptide is also presented on healthy tissues, potentially leading to severe adverse events (Journal for ImmunoTherapy of Cancer, 2022; PMID: 35641009).

Other names

Peptide-MHC complexpMHCHLA-peptide complexTumor antigen-HLA complexpMHC complexAntigen-MHC complex

Binding of engineered T-cell receptors (TCRs) or TCR-mimic antibodies to the specific peptide-MHC complex on the tumor cell surface, leading to T-cell recruitment, activation, and subsequent granzyme/perforin-mediated lysis of the cancer cell.