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

The H3.3K27M mutant peptide presented by HLA-A*02:01 is a tumor-specific neoantigen complex that serves as a critical therapeutic target in neuro-oncology. It arises from a somatic point mutation in the H3F3A gene, which replaces lysine with methionine at position 27 of the Histone H3.3 protein, a hallmark of aggressive diffuse midline gliomas (DMGs) such as diffuse intrinsic pontine glioma (DIPG). This mutation disrupts the Polycomb Repressive Complex 2 (PRC2) and leads to global loss of H3K27 trimethylation, driving oncogenic gene expression. The resulting mutant decamer peptide (RMSAPSTGGV) is processed and presented by the HLA-A*02:01 major histocompatibility complex (MHC) class I molecule on the surface of malignant cells. As a target, this complex is highly attractive for immunotherapy because the K27M mutation is entirely absent in normal tissues, providing a narrow window for precision targeting. Current clinical strategies include the use of synthetic peptide vaccines, often combined with adjuvants like Poly ICLC or checkpoint inhibitors like Nivolumab, to stimulate endogenous T-cell responses. Additionally, adoptive cell therapies, including T-cell receptor (TCR) engineered T-cells and TCR-mimic chimeric antigen receptor (CAR) T-cells, are under investigation to directly target the complex. However, recent studies have raised concerns regarding the low density of endogenous presentation of this peptide on tumor surfaces, which may limit the efficacy of some T-cell-based approaches.

Other names

H3.3K27M(26-35) peptide-HLA-A*02:01 complexH3F3A K27M neoantigenHLA-A*02:01-restricted H3.3K27M epitopeH3.3K27M-MHC class I complexRMSAPSTGGV-HLA-A*02:01 complex

The target is a neoantigen complex where a mutant fragment of the Histone H3.3 protein (containing the K27M substitution) is displayed on the cell surface by the HLA-A*02:01 molecule. Therapeutic agents such as peptide vaccines or engineered T-cells (TCR-T or CAR-T) are designed to recognize this specific peptide-MHC complex, triggering a cytotoxic immune response that selectively destroys tumor cells while sparing healthy cells that lack the mutation.