Tumor-specific neoantigen–Major Histocompatibility Complex (neoAg-MHC) (neoAg-MHC)

Tumor-specific neoantigen–Major Histocompatibility Complex (neoAg-MHC) complexes are molecular structures formed when mutated protein fragments, unique to cancer cells, are processed and presented on the cell surface by MHC molecules (NCI, 2023). Unlike tumor-associated antigens, which are also found in normal tissues, neoantigens arise from somatic mutations such as single nucleotide variants, indels, or gene fusions, making them truly foreign to the immune system and reducing the risk of central tolerance (Nature Reviews Drug Discovery, 2021). These complexes serve as the primary targets for T-cell receptors (TCRs) on cytotoxic T lymphocytes, which can trigger a potent and specific anti-tumor immune response (Science, 2022). In therapeutic contexts, neoAg-MHC complexes are targeted through personalized cancer vaccines, adoptive cell transfer of TCR-engineered T cells (TCR-T), and TCR-mimetic antibodies or bispecifics (Frontiers in Immunology, 2020). The high specificity of these targets offers the potential for high efficacy with minimal off-target toxicity, although challenges remain regarding HLA down-regulation and the heterogeneity of neoantigen expression within tumors (Journal of Hematology & Oncology, 2021).

Other names

Neoantigen-HLA complexNeoepitope-MHC complexMutant peptide-MHC complexTumor-specific antigen-MHC complexTSA-MHC complex

Therapeutic agents target these complexes by either delivering the neoantigen as a vaccine to prime endogenous T cells or by providing engineered T cells (TCR-T) that express a receptor specifically tuned to the neoAg-MHC complex, leading to direct tumor cell lysis (Nature Reviews Drug Discovery, 2021).