Patient-specific neoepitope–Human Leukocyte Antigen complex (Neoantigen-HLA complex) (Neoantigen-HLA complex)

A patient-specific neoepitope–HLA complex is a unique molecular target formed when a tumor-specific mutation results in a novel peptide (neoepitope) that is processed and presented on the cell surface by the patient's own Human Leukocyte Antigen (HLA) molecules (Nature, 2017, doi:10.1038/nature23003). Unlike shared tumor antigens, these complexes are entirely unique to the individual's tumor, making them highly specific targets for personalized immunotherapy (Science, 2023, doi:10.1126/science.ade2148). They are primarily recognized by the T-cell receptor (TCR) of CD8+ cytotoxic T cells, triggering a targeted immune response against the cancer cells while sparing healthy tissue (NEJM, 2023, doi:10.1056/NEJMoa2215140). Therapeutic strategies targeting these complexes include personalized mRNA or peptide vaccines, which prime the immune system to recognize the neoepitope, and adoptive cell therapies using TCR-engineered T cells (Nature Medicine, 2024, doi:10.1038/s41591-023-02769-8). Because these targets are not expressed in normal tissues, they offer a high safety profile regarding off-tumor toxicity, although challenges remain in identifying the most immunogenic neoepitopes and overcoming tumor-mediated immune evasion (Cell, 2021, doi:10.1016/j.cell.2021.04.033).

Other names

Tumor-specific neoantigen-HLA complexNeoepitope-MHC complexPersonalized neoantigen-HLA complexTSA-HLA complexpHLA complex

Recognition of the neoepitope-HLA complex by the T-cell receptor (TCR) triggers the activation and proliferation of tumor-specific cytotoxic T lymphocytes (CTLs), leading to targeted lysis of tumor cells expressing the specific mutation.