Peptide-Major Histocompatibility Complex class I presenting tumor neoantigens (pMHC-I neoantigen complex)

Peptide-Major Histocompatibility Complex class I (pMHC-I) complexes presenting tumor neoantigens are molecular assemblies on the surface of cancer cells that display fragments of mutated proteins to the immune system (Schumacher & Schreiber, Science 2015). These complexes are composed of a polymorphic HLA class I heavy chain, beta-2-microglobulin, and a 8-11 amino acid peptide derived from a tumor-specific somatic mutation (Blass & Ott, Nature Reviews Clinical Oncology 2021). Because these neoantigens are absent from normal tissues, they serve as highly specific 'non-self' signals that can be recognized by CD8+ T-cell receptors (TCRs) without the constraints of central tolerance (Sahin & Türeci, Science 2018). This specificity makes them ideal targets for personalized cancer immunotherapies, including mRNA-based vaccines and TCR-engineered T-cell therapies. However, the effectiveness of targeting these complexes can be limited by the heterogeneity of mutations within a tumor and the ability of cancer cells to downregulate MHC expression to evade immune detection (Garrido et al., Cancer Immunology, Immunotherapy 2016). Current clinical efforts focus on identifying high-affinity neoepitopes and developing platforms that can rapidly produce patient-specific treatments to overcome these challenges.

Other names

Neoantigen-MHC complexesTumor-specific antigen-MHC complexesNeoepitope-HLA complexespMHC-I neoantigensTumor-specific pMHC

Therapeutic agents target these complexes either by inducing their presentation (vaccines) or by providing synthetic receptors (TCR-T, TCR-like antibodies) that recognize the specific peptide-MHC binding groove to trigger T-cell mediated cytotoxicity.