Tumor-associated antigen and neoantigen-MHC complex

Tumor-associated antigens (TAAs) and neoantigen-MHC complexes are the primary molecular targets recognized by T-cell receptors (TCRs) in the context of adoptive cell therapies, such as tumor-infiltrating lymphocyte (TIL) therapy and TCR-engineered T-cell (TCR-T) therapy. TAAs are self-proteins that are either overexpressed in tumors or expressed in a lineage-specific or developmental-stage-specific manner (e.g., cancer-testis antigens like MAGE-A4), whereas neoantigens are unique peptides derived from somatic mutations within the tumor genome (Schumacher & Schreiber, 2015). These antigens are processed into short peptides and presented on the cell surface by Major Histocompatibility Complex (MHC) molecules, forming a peptide-MHC (pMHC) complex (Rosenberg & Restifo, 2015). The interaction between the TCR and the pMHC complex is highly specific and serves as the critical trigger for T-cell mediated cytotoxicity against malignant cells. Therapeutic agents like Lifileucel (Amtagvi) utilize the natural repertoire of TILs to target these complexes, while TCR-T therapies like Afamitresgene autoleucel are engineered to target specific TAAs (FDA, 2024; Adaptimmune, 2024). Clinical challenges include the potential for on-target, off-tumor toxicity if the target antigen is present on healthy tissues, as well as tumor evasion through the down-regulation of MHC molecules (Linette et al., 2013).

Other names

Tumor-specific antigenTSAPeptide-MHC complexpMHCCancer-germline antigenMutated self-antigenNeoepitope

Recognition of the peptide-MHC complex by the T-cell receptor (TCR) triggers a signaling cascade through the CD3 complex, leading to T-cell activation, secretion of pro-inflammatory cytokines (e.g., IFN-gamma), and the release of cytotoxic granules (perforin and granzymes) that induce apoptosis in the target tumor cell (Rosenberg & Restifo, 2015).