Patient-specific neoantigen peptides presented on Major Histocompatibility Complex class I (Neoantigen-MHC-I)

Patient-specific neoantigen peptides presented on Major Histocompatibility Complex class I (MHC-I) represent a frontier in personalized oncology. These targets are short peptides (typically 8-11 amino acids) derived from somatic mutations unique to an individual's tumor, which are processed and displayed on the cell surface by MHC-I molecules for recognition by CD8+ cytotoxic T cells [1, 3]. Because these neoantigens are absent from healthy tissues, they are not subject to central thymic tolerance, making them highly immunogenic and ideal targets for precision immunotherapy with minimal off-target effects [3, 7]. Therapeutic interventions targeting these complexes include personalized mRNA or peptide vaccines (e.g., mRNA-4157, Autogene cevumeran) and adoptive cell therapies using T-cell receptors (TCRs) engineered to recognize specific neoantigen-MHC-I combinations [5, 11]. These treatments aim to overcome 'immunological ignorance' or exhaustion by expanding the repertoire of neoantigen-specific T cells capable of infiltrating the tumor microenvironment and inducing apoptosis in malignant cells [7, 9]. However, challenges remain, including the potential for tumor immune evasion via the loss of antigen presentation machinery and the significant logistical hurdles associated with the rapid, patient-specific manufacturing required for these therapies [10, 11].

Other names

Tumor-specific neoantigens (TSNAs)NeoepitopesMutation-derived antigenspHLA (peptide-HLA) complexesTumor-specific antigens (TSAs)Personalized neoantigens

Personalized immunotherapy strategies, such as mRNA vaccines or adoptive T-cell transfers, aim to induce or enhance a cytotoxic CD8+ T-cell response specifically against these unique peptide-MHC complexes. Vaccines provide the genetic code or peptides for these neoantigens to prime the immune system, while TCR-T therapies provide engineered T cells that directly recognize the neoantigen-MHC-I complex on the tumor surface, leading to selective tumor cell lysis.