Tumor-specific neoantigen peptides presented on MHC class I and II (TSNA)

Tumor-specific neoantigens (TSNAs) are unique peptides resulting from non-synonymous somatic mutations, such as point mutations, insertions/deletions, or chromosomal translocations, that occur exclusively within tumor cells (PubMed: 29739835). These mutated proteins are processed by the proteasome and presented on the cell surface by Major Histocompatibility Complex (MHC) class I and class II molecules to be surveyed by the immune system (Nature: 10.1038/s41568-019-0133-1). Because TSNAs are not expressed in normal tissues, they bypass central thymic tolerance, making them highly immunogenic and reducing the risk of autoimmune cross-reactivity compared to tumor-associated antigens (TAAs). In clinical practice, these neoantigens are targeted using personalized immunotherapy platforms, including mRNA-based vaccines and adoptive T-cell transfers, which aim to prime or augment the patient's own T-cell response against the malignancy (Science: 10.1126/science.aau5905). The efficacy of these treatments often depends on the fitness of the neoantigen, its binding affinity to the patient's specific HLA alleles, and the overall tumor mutational burden. Despite their promise, challenges remain, including the high heterogeneity of neoantigen expression within tumors and the potential for immune evasion through the downregulation of MHC molecules.

Other names

Tumor neoantigensNeoepitopesMutation-derived antigensTumor-specific antigens (TSA)Somatic mutation-derived antigenspMHC complexes

Personalized vaccines or cell therapies targeting these complexes stimulate the expansion of neoantigen-specific CD8+ and CD4+ T cells. These T cells recognize the specific peptide-MHC complex on the surface of tumor cells, leading to targeted cell lysis and the release of further antigens to broaden the immune response.