Tumor-associated antigen peptide–Major Histocompatibility Complex (TAA-pMHC) (TAA-pMHC)

Tumor-associated antigen peptide–Major Histocompatibility Complex (TAA-pMHC) complexes are the fundamental units of recognition for the adaptive cellular immune system on the surface of malignant cells. These complexes consist of short peptide fragments, derived from intracellular proteins that are either mutated (neoantigens) or overexpressed (TAAs), loaded onto MHC (or HLA in humans) molecules (Source: Nature Reviews Immunology, 2021). In the context of oncology, these complexes serve as the primary targets for T-cell-based immunotherapies, including T-cell receptor (TCR) engineered T cells and bispecific T-cell engagers. Unlike traditional antibody targets that are restricted to surface proteins, pMHC complexes allow the immune system to monitor the internal proteome of the tumor cell, significantly expanding the range of targetable antigens (Source: Frontiers in Oncology, 2020). Therapeutic strategies targeting these complexes, such as the approved drug Tebentafusp, aim to trigger the selective destruction of tumor cells by cytotoxic T lymphocytes while sparing healthy tissues (Source: New England Journal of Medicine, 2021). However, the effectiveness of these therapies is often limited by the heterogeneity of antigen expression and the potential for HLA downregulation as a mechanism of immune escape (Source: Journal for ImmunoTherapy of Cancer, 2022). Furthermore, ensuring high specificity is critical to avoid lethal off-target toxicity, which can occur if the targeted peptide sequence is shared with proteins in vital organs (Source: Molecular Therapy, 2013).

Other names

pMHC complexHLA-peptide complexTumor-specific antigen-MHC complexNeoantigen-MHC complexAntigenic peptide-MHC complexTumor-associated antigen peptide–MHC complexes on autologous tumor cells

Recognition of specific peptide-MHC complexes by T-cell receptors (TCRs) or TCR-mimetic molecules, leading to the recruitment and activation of cytotoxic T lymphocytes to induce apoptosis in the target tumor cell.