HLA-A*02:01-restricted Histone H3.3 K27M neoantigen (H3.3K27M-HLA-A*02:01) (H3.3K27M-HLA-A*02:01)

The HLA-A*02:01-presented H3.3K27M neoantigen is a tumor-specific peptide-MHC complex that serves as a critical target for immunotherapy in high-grade midline gliomas (Chheda et al., 2018). This complex is formed when the mutant Histone H3.3 protein, featuring a lysine-to-methionine substitution at position 27 (K27M), is processed into peptides and presented on the cell surface by the HLA-A*02:01 allele. The H3.3K27M mutation is a pathognomonic driver found in over 80% of diffuse intrinsic pontine gliomas (DIPG), a lethal pediatric brain cancer (Mueller et al., 2019). Because this neoantigen is entirely absent from normal tissues, it provides an ideal window for precision medicine, minimizing the risk of systemic autoimmunity. Current therapeutic approaches targeting this complex include peptide vaccines and adoptive cell therapies using T-cell receptors (TCRs) engineered to recognize the specific mutant epitope. Clinical efficacy depends on both the presence of the H3.3K27M mutation and the patient's HLA-A*02:01 genotype, making these essential biomarkers for patient selection. Research has demonstrated that specific TCRs can recognize this complex with high affinity, leading to potent cytotoxic T-lymphocyte responses against tumor cells. However, therapeutic challenges include the blood-brain barrier and the risk of neuroinflammation within the delicate brainstem environment.

Other names

H3.3K27M peptide-MHC complexHLA-A*02:01/H3.3K27MHistone H3.3 K27M neoepitopeH3.3K27M(26-35) neoantigen

T-cell receptor (TCR) mediated recognition of the mutant peptide-MHC complex leading to cytotoxic T-cell activation and tumor cell lysis (Chheda et al., 2018).