Tumor neoantigen-derived peptide-Major Histocompatibility Complex (NeoAg-MHC)

Tumor neoantigen-derived peptides presented on the Major Histocompatibility Complex (MHC) are unique molecular signatures resulting from somatic mutations within a tumor's genome. These mutations, which include single nucleotide variants, indels, and frameshifts, produce novel protein sequences that are processed and displayed on the cell surface by MHC Class I or II molecules (Blass & Ott, 2021, Nature Reviews Clinical Oncology). Because these neoantigens are entirely absent from normal, healthy tissues, they serve as ideal targets for precision immunotherapy, minimizing the risk of central tolerance and autoimmune cross-reactivity. Recognition of these peptide-MHC (pHLA) complexes by the T-cell receptor (TCR) is the fundamental step in the adaptive immune system's ability to identify and eliminate malignant cells (Schumacher & Schreiber, 2015, Science). Current therapeutic strategies targeting these complexes include personalized mRNA and peptide vaccines designed to prime the patient's own immune system, as well as adoptive cell therapies like TCR-engineered T cells (TCR-T) and tumor-infiltrating lymphocytes (TILs). These therapies aim to induce a robust, tumor-specific CD8+ and CD4+ T-cell response to achieve durable clinical outcomes (Xie et al., 2023, Frontiers in Immunology). Despite their promise, challenges remain, including the high degree of inter-patient heterogeneity and the potential for tumor escape through HLA downregulation or loss of heterozygosity. Furthermore, the identification of truly immunogenic neoepitopes requires sophisticated bioinformatic pipelines and HLA binding affinity predictions. Overall, targeting neoantigen-MHC complexes represents a cornerstone of the next generation of personalized oncology.

Other names

NeoepitopeTumor-specific antigen (TSA)pHLA complexNeoantigen-HLA complexMutation-derived antigenNeoantigen-derived peptide-MHC

Drugs targeting these complexes function by either priming the host immune system to recognize these unique sequences via vaccination or by providing engineered T-cells (TCR-T) or bispecific molecules that directly bind the peptide-MHC complex to induce targeted tumor cell lysis (Schumacher & Schreiber, 2015, Science; Blass & Ott, 2021, Nature Reviews Clinical Oncology).