neoantigener

Neoantigener are peptides that arise from tumor-specific mutations and are not found in normal tissues. These novel epitopes are generated when somatic alterations alter protein coding sequences or RNA processing, creating new peptide sequences that can be presented by major histocompatibility complex (MHC) molecules to the immune system. Sources include missense mutations, frameshifts, nonsense mutations, gene fusions, alternative splicing, and, in some cases, RNA editing.

For presentation and recognition, neoantigener are displayed on MHC class I molecules to CD8+ T cells, and can be presented by MHC class II to CD4+ T cells under appropriate conditions. Their immunogenicity depends on factors such as the abundance and processing of the mutated peptide, the binding affinity to the patient's HLA alleles, and the ability of T cells to recognize the peptide as non-self. Clonality within the tumor and the overall immunosuppressive microenvironment influence the likelihood of an effective immune response.

Clinical relevance is most evident in oncology. A higher neoantigen load, particularly clonal neoantigens present in most tumor cells, has been associated with better responses to immune checkpoint inhibitors in several cancer types. Neoantigener are also central to personalized cancer vaccines and adoptive T cell therapies, where vaccines or engineered T cells target patient-specific neoantigen peptides identified through tumor sequencing and validation assays.

Challenges include intratumoral heterogeneity, limited antigen presentation, and tumor immune evasion. Predicting immunogenic neoantigener with high accuracy remains complex, and comprehensive validation is often required before clinical application.