Tumor neoantigen-Major Histocompatibility Complex (MHC) complex (NeoAg-MHC)

Patient-specific tumor neoantigens are unique peptides derived from non-synonymous somatic mutations, such as single nucleotide variants or frameshifts, that occur exclusively within the tumor genome (Schumacher & Schreiber, 2015, Nature Reviews Cancer). These neoepitopes are processed by the intracellular machinery and presented on the cell surface by Major Histocompatibility Complex (MHC) Class I or II molecules (Sahin & Türeci, 2018, Science). Because these antigens are not expressed in healthy tissues, they bypass central thymic tolerance, making them highly potent targets for the immune system with a low risk of systemic autoimmunity (Ott et al., 2017, NEJM). Therapeutic interventions targeting these complexes include personalized cancer vaccines (mRNA, peptide, or viral vectors) and adoptive T-cell therapies using TCR-engineered cells (Hu et al., 2021, Nature Reviews Clinical Oncology). These drugs work by expanding the pool of neoantigen-specific T cells that can recognize and kill tumor cells presenting the specific pMHC complex. However, the effectiveness of this approach can be limited by tumor heterogeneity, the loss of HLA expression, or the presence of an immunosuppressive tumor microenvironment (Blass & Ott, 2021, Nature Reviews Clinical Oncology).

Other names

Personalized tumor antigensNeoepitopesMutation-derived antigensTumor-specific antigensTSAsPeptide-MHC complexpMHC

Drugs targeting these complexes function by either actively immunizing the patient to generate a de novo T-cell response (personalized vaccines) or by providing exogenously engineered T cells (TCR-T therapy) that specifically bind the neoantigen-MHC complex, leading to the release of perforins and granzymes and subsequent tumor cell lysis (Sahin & Türeci, 2018, Science; Hu et al., 2021, Nature Reviews Clinical Oncology).