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

Tumor-associated antigen (TAA)-derived peptides presented on Major Histocompatibility Complex (MHC) molecules are a pivotal class of targets in immuno-oncology, enabling the immune system to recognize intracellular proteins. These targets consist of short peptide fragments, processed from cellular proteins and displayed on the cell surface by MHC (or HLA in humans) molecules. Unlike conventional monoclonal antibodies that target surface-bound proteins, TAA-MHC complexes provide access to the entire cellular proteome, including cancer-testis antigens, differentiation antigens, and overexpressed proteins. Therapeutic interventions such as TCR-engineered T-cells (TCR-T) and TCR-bispecific engagers are designed to bind these complexes with high specificity. However, clinical utility is restricted by the requirement for specific HLA genotypes in patients and the risk of cross-reactivity with similar peptides in healthy tissues. Furthermore, tumors may develop resistance through the downregulation of MHC machinery, complicating long-term efficacy (Yuan et al., 2021, Frontiers in Immunology).

Other names

pHLAPeptide-HLA complexTumor-associated antigen-MHC complexMHC-restricted tumor antigenTumor-specific peptide-MHC

Recognition of the peptide-MHC complex by engineered T-cell receptors (TCRs) or TCR-mimetic bispecific molecules, leading to the activation of cytotoxic T-lymphocytes and subsequent lysis of the tumor cell (Nathan et al., 2021, NEJM; D'Angelo et al., 2024, Lancet).