Patient-specific tumor-associated neoantigen presented as peptide–MHC complex (Neoantigen-MHC)

Patient-specific tumor-associated neoantigens presented as peptide–MHC (pMHC) complexes are highly specific therapeutic targets that arise from non-synonymous somatic mutations unique to an individual's tumor cells (Schumacher & Schreiber, 2015, Science). These mutations result in novel protein sequences that are processed into short peptides and displayed on the cell surface by Major Histocompatibility Complex (MHC) molecules, also known as Human Leukocyte Antigens (HLA) in humans (Blass & Ott, 2021, Nature Reviews Clinical Oncology). Because these neoantigens are entirely absent from healthy tissues, they are not subject to central thymic tolerance, making them ideal triggers for a robust and highly specific T-cell mediated immune response (Sahin & Türeci, 2018, Science). Therapeutic interventions targeting these complexes include personalized cancer vaccines—such as mRNA, DNA, or peptide-based platforms—and adoptive cell therapies using T-cell receptors (TCRs) engineered to recognize specific pMHC combinations (Xie et al., 2023, Signal Transduction and Targeted Therapy). These strategies aim to expand the repertoire of neoantigen-specific T cells to recognize and eliminate malignant cells while sparing healthy tissue. However, the effectiveness of targeting these complexes can be limited by intra-tumoral heterogeneity, the low frequency of truly immunogenic mutations, and the ability of tumors to downregulate MHC expression as a mechanism of immune escape.

Other names

NeoantigenTumor-specific antigen (TSA)NeoepitopepHLA complexMutation-derived antigenPersonalized tumor antigen

Induction of de novo T-cell responses against tumor-specific mutations and redirection of cytotoxic T lymphocytes to recognize and eliminate neoantigen-expressing tumor cells.