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

The Tumor-associated antigen-Major Histocompatibility Complex (TAA-MHC) complex 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 molecule (Human Leukocyte Antigen or HLA in humans). This complex is presented on the surface of cancer cells and serves as the primary ligand for T-cell receptors (TCRs), allowing the immune system to detect intracellular oncogenic transformations (Rock et al., 2016, Nature Immunology). MHC Class I complexes typically present endogenous antigens to CD8+ cytotoxic T-cells, while MHC Class II complexes present antigens to CD4+ helper T-cells. In modern oncology, these complexes are the focal point for TCR-engineered T-cell therapies (TCR-T) and bispecific T-cell engagers like Tebentafusp, which targets the gp100 peptide presented by HLA-A*02:01 (Nathan et al., 2021, NEJM). By targeting the pMHC complex, therapies can address intracellular targets that are otherwise inaccessible to traditional monoclonal antibodies. However, the efficacy of these treatments is often restricted by the patient's specific HLA haplotype and the potential for lethal cross-reactivity if the targeted peptide sequence is shared by proteins in healthy tissues, such as the heart or brain (Adaptimmune, 2024, Tecelra Prescribing Information).

Other names

Peptide-MHC complexpMHCTumor antigen-HLA complexNeoantigen-MHC complexpHLA complex

Engagement of T-cell receptors (TCRs) or TCR-mimetic molecules to recognize specific intracellularly derived peptides presented on the cell surface, thereby triggering T-cell mediated lysis of the target cell.