Tumor-associated antigen-Major Histocompatibility Complex-T-cell receptor complex (TAA-MHC-TCR complex) (TAA-MHC-TCR complex)

The Tumor-associated antigen-Major Histocompatibility Complex-T-cell receptor (TAA-MHC-TCR) complex is the central molecular assembly required for the adaptive immune system to identify and eliminate cancer cells (Rossjohn et al., 2015, Annual Review of Immunology). This complex consists of a processed intracellular peptide (the antigen) bound within the groove of a Major Histocompatibility Complex (MHC) molecule on the tumor cell surface, which is then recognized by a specific T-cell receptor (TCR) on a T lymphocyte. Unlike traditional antibody-based therapies that only target surface proteins, the TAA-MHC-TCR interface allows the immune system to see the internal proteome of the cell, including oncogenic drivers and cancer-testis antigens (Altman et al., 1996, Science). Therapeutic interventions targeting this complex include TCR-engineered T-cell (TCR-T) therapies, such as Afamitresgene autoleucel, and bispecific TCR-based engagers like Tebentafusp (Nathan et al., 2021, NEJM; Merchant et al., 2024, The Lancet). These drugs are designed to bypass natural immune tolerance or low-affinity endogenous TCRs to mount a potent cytotoxic response against tumors. However, clinical application is limited by the requirement for specific patient HLA types and the significant risk of off-target toxicity if the TCR cross-reacts with similar peptides in healthy tissues (D'Angelo et al., 2018, Cancer Discovery).

Other names

pMHC-TCR complexPeptide-MHC-TCR complexAntigen-MHC-TCR synapseTCR-pMHC interaction

TCR-engineered T-cell therapy (TCR-T) or TCR-bispecific engagers (ImmTACs) that bind the pMHC complex to trigger T-cell mediated lysis of tumor cells.