Histone H3.3 K27M neoantigen presented by HLA-A*02:01 (H3.3-K27M/HLA-A*02:01)

The H3.3-K27M neoantigen presented by HLA-A*02:01 is a highly specific tumor target found in pediatric diffuse midline gliomas (DMGs), including diffuse intrinsic pontine glioma (DIPG) (Chheda et al., 2018, Nature). This target arises from a recurrent somatic mutation in the H3F3A gene, where lysine 27 of histone H3.3 is replaced by methionine (K27M), a driver mutation present in the majority of these aggressive brain tumors (Mueller et al., 2019, JCI Insight). The mutant peptide is processed and displayed on the cell surface by the HLA-A*02:01 major histocompatibility complex (MHC) molecule, creating a unique epitope for T-cell recognition (Ochs et al., 2017, OncoImmunology). Because the K27M mutation is entirely tumor-specific and absent in healthy tissues, it represents an ideal neoantigen for precision immunotherapy. Current therapeutic strategies include peptide vaccines (e.g., NCT02960230) and T-cell receptor (TCR)-engineered T-cell therapies designed to recognize and kill cells expressing this specific peptide-MHC complex. Despite its promise, clinical efficacy is challenged by the blood-brain barrier, the immunosuppressive tumor microenvironment, and the critical location of these tumors in the brainstem (Schumacher & Schreiber, 2015, Science).

Other names

H3.3K27M-HLA-A*02:01 complexH3F3A K27M neoantigenK27M-restricted neoantigenHistone H3.3 lysine 27-to-methionine mutation-derived peptide

Induction of T-cell mediated cytotoxicity against tumor cells presenting the H3.3-K27M mutant peptide via the HLA-A*02:01 complex.