Mutant neoantigen peptide–Human Leukocyte Antigen (HLA) class I complex (Neoantigen-HLA-I complex)

Mutant neoantigen peptide–Human Leukocyte Antigen (HLA) class I complexes are specialized cell-surface structures that play a pivotal role in the immune system's ability to identify and eliminate cancer cells. These complexes consist of a short peptide fragment, derived from a tumor-specific somatic mutation, nested within the binding groove of an HLA class I molecule (Schumacher & Schreiber, 2015, Science). Because these mutated peptides are not found in the normal human proteome, they are recognized as non-self by the T-cell receptors (TCRs) of CD8+ cytotoxic T cells, making them highly attractive targets for precision immunotherapy (Blass & Ott, 2021, Nature Reviews Clinical Oncology). Therapeutic interventions targeting these complexes include personalized neoantigen vaccines, which prime the immune system to recognize these unique markers, and adoptive T-cell therapies using TCR-engineered T cells (TCR-T) designed to bind specific mutation-HLA combinations (Yarchoan et al., 2017, NEJM). While these targets offer high specificity and reduced risk of auto-immunity compared to shared tumor antigens, their clinical utility is challenged by the vast diversity of HLA alleles across the population and the potential for tumors to evade the immune response by downregulating HLA expression or losing the target mutation (Finn, 2018, NEJM). Current research focuses on identifying high-affinity neoepitopes and developing off-the-shelf TCR-T therapies for common mutations like KRAS and TP53.

Other names

Tumor-specific neoantigen-MHC complexNeoepitope-HLA complexMutant peptide-MHC class I complexTSA-HLA complexNeoantigen-MHC-I

Recognition of the specific mutant peptide-HLA complex by endogenous or engineered T-cell receptors (TCRs), which triggers the formation of an immunological synapse, T-cell degranulation, and the release of perforins and granzymes to induce apoptosis in the target tumor cell.