Tumor neoantigen–Major Histocompatibility Complex (MHC) complex (Neoantigen-MHC)

Tumor neoantigen–Major Histocompatibility Complex (MHC) complexes are molecular structures presented on the surface of malignant cells, consisting of a somatic mutation-derived peptide (neoepitope) bound to an MHC molecule (HLA in humans). These complexes are central to the cancer-immunity cycle, as they allow the immune system to distinguish tumor cells from healthy cells through T-cell receptor (TCR) recognition (Chen & Mellman, 2013, Nature). Because neoantigens are absent from the normal proteome, they are considered ideal targets for precision immunotherapy, offering high specificity and reduced risk of central tolerance (Schumacher & Schreiber, 2015, Science). Current therapeutic approaches include personalized mRNA or DNA vaccines designed to prime the immune system against these complexes, as well as adoptive cell therapies using TCR-engineered T-cells (TCR-T) (Blass & Ott, 2021, Nature Reviews Clinical Oncology). Despite their promise, the effectiveness of targeting these complexes can be hindered by tumor heterogeneity and the loss of MHC expression, which serves as a common mechanism of acquired resistance (Sahin & Türeci, 2018, Science). Advanced computational algorithms and immunopeptidomics are increasingly used to identify and prioritize the most immunogenic neoantigen-MHC complexes for clinical intervention (Zhang et al., 2024, Frontiers in Immunology).

Other names

Neoepitope-MHC complexTumor-specific antigen (TSA)-MHC complexpeptide-HLA (pHLA) complexpMHC complexMutant peptide-MHC complex

Recognition of the specific peptide-MHC complex by T-cell receptors (TCRs) on CD8+ or CD4+ T-cells, or by TCR-mimetic antibodies, to induce cytotoxic T-lymphocyte mediated lysis of the tumor cell.