Tumor-associated antigens and neoantigens presented on peptide-MHC complexes (TAA/Neoantigen-pMHC)

Tumor-associated antigens (TAAs) and neoantigens presented on peptide-major histocompatibility complexes (pMHC) are the primary targets for modern T-cell-based cancer immunotherapies [Nature Reviews Cancer, 2017]. TAAs are self-antigens with abnormal expression patterns in tumors, such as overexpressed proteins or cancer-testis antigens, while neoantigens are novel peptides resulting from tumor-specific DNA mutations [NCI Dictionary]. These peptides are processed intracellularly and displayed on the cell surface by MHC molecules, forming a pMHC complex that can be recognized by T-cell receptors (TCRs) [Frontiers in Immunology, 2020]. Therapeutic strategies targeting these complexes include TCR-engineered T-cells (TCR-T), bispecific T-cell engagers like Tebentafusp, and personalized mRNA vaccines [FDA, 2022; NEJM, 2023]. By targeting pMHC, these drugs aim to direct the cytotoxic power of the immune system specifically against malignant cells while sparing healthy tissue. However, the effectiveness of these therapies can be limited by tumor heterogeneity and the loss of MHC expression, which allows tumors to evade immune detection [Nature Reviews Immunology, 2019]. Additionally, targeting TAAs carries a risk of off-target toxicity if the antigen is present on vital healthy organs [Journal of Clinical Oncology, 2015].

Other names

Tumor-specific antigensTSANeoepitopesCancer-testis antigenspMHC complexesMutated self-antigens

Therapeutic agents recognize specific peptide fragments displayed within the groove of Major Histocompatibility Complex (MHC) molecules on the tumor cell surface, typically using engineered T-cell receptors (TCRs) or TCR-mimetic antibodies to trigger T-cell mediated cytotoxicity [Nature Reviews Drug Discovery, 2021].