Neoantigen-Major Histocompatibility Complex (NeoAg-MHC)

Patient-specific neoantigen–MHC complexes are unique molecular structures formed when peptides derived from tumor-specific somatic mutations are presented on the cell surface by Major Histocompatibility Complex (MHC) molecules (Schumacher & Schreiber, 2015). These complexes are essential for the immune system's ability to distinguish malignant cells from healthy tissue, as neoantigens are not expressed in normal cells and thus bypass central thymic tolerance (Blass & Ott, 2021). Recognition of these complexes by the T-cell receptor (TCR) of CD8+ or CD4+ T cells triggers a targeted immune response, leading to the destruction of the tumor cell (Yadav et al., 2014). In therapeutic applications, these complexes serve as the basis for personalized cancer vaccines, such as mRNA-4157, and adoptive cell therapies like TCR-engineered T cells (TCR-T), which are designed to enhance the patient's natural anti-tumor immunity (Sahin & Türeci, 2018). These therapies rely on the precise identification of mutations through whole-exome sequencing and the prediction of peptide-MHC binding affinity (Ott et al., 2017). Despite their high specificity, the effectiveness of targeting these complexes can be limited by tumor heterogeneity and the downregulation of MHC molecules by cancer cells (Hu et al., 2021). Furthermore, there is a potential risk for off-target cross-reactivity if the neoantigen shares structural similarities with wild-type peptides found in healthy tissues (Linette et al., 2013). Overall, these complexes represent a cornerstone of precision oncology, offering a pathway to highly individualized and potent immunotherapy (Zhang et al., 2021).

Other names

Tumor-specific neoantigenNeoepitope-HLA complexMutant peptide-MHC complexpHLA complexTumor-specific antigen (TSA)

Presentation of tumor-specific mutant peptides via MHC molecules to facilitate recognition and lysis by T-cell receptor (TCR) bearing T cells.