Tumor-associated antigen-derived peptide-MHC class I complex (TAA-pMHC-I)

Tumor-associated antigen (TAA)-derived peptides presented on Major Histocompatibility Complex (MHC) class I molecules are essential targets for modern cancer immunotherapy. These complexes are formed when intracellular proteins, such as cancer-testis antigens or mutated neoantigens, are processed by the proteasome and loaded onto MHC class I molecules within the endoplasmic reticulum (Nature Reviews Immunology, 2019). Once transported to the cell surface, these peptide-MHC (pMHC) complexes act as specific ligands for the T-cell receptors (TCRs) of CD8+ cytotoxic T lymphocytes, facilitating the recognition and destruction of malignant cells (Journal of Hematology & Oncology, 2023). Unlike traditional antibody targets that must be surface-expressed proteins, pMHC complexes allow the immune system to "see" the internal proteome of the tumor cell. Therapeutic interventions targeting these complexes include TCR-engineered T-cell (TCR-T) therapies, such as Afamitresgene autoleucel, and bispecific TCR-based T-cell engagers like Tebentafusp (FDA, 2022; FDA, 2024). A significant challenge in targeting these complexes is the requirement for specific HLA alleles (HLA restriction) and the risk of lethal cross-reactivity if the targeted peptide sequence is shared with proteins in vital organs (Blood, 2013).

Other names

Tumor-associated antigen-peptide-HLA complexpMHC-I complexCancer-testis antigen-MHC complexNeoantigen-MHC complexHLA-restricted tumor antigenPeptide-HLA-A*02:01 complex

Direct binding of engineered T-cell receptors (TCRs), bispecific TCR-based engagers, or TCR-mimetic antibodies to the specific peptide-MHC complex on the tumor cell surface, which triggers T-cell activation, cytokine release, and cytotoxic lysis of the target cell.