HLA-A*02:01-restricted histone H3.3-K27M neoantigen complex (HLA-A*02:01/H3.3-K27M)

The HLA-A*02:01-restricted histone H3.3-K27M neoantigen complex is a tumor-specific antigen found on the surface of malignant cells in diffuse midline gliomas (DMGs), including diffuse intrinsic pontine glioma (DIPG) (Chheda et al., 2018, Nature). This complex is formed when the mutant histone H3.3 protein, carrying a lysine-to-methionine substitution at position 27 (K27M), is processed and the resulting 10-amino acid neoepitope (RMSAPATGGV) is loaded onto the HLA-A*02:01 molecule (Mueller et al., 2019, JCI). The H3.3-K27M mutation is a hallmark driver mutation present in over 70% of pediatric DMGs and is absent in normal tissues, making it a highly specific target for precision immunotherapy (Wu et al., 2012, Nature Genetics). Therapeutic strategies targeting this complex include TCR-engineered T-cell therapies and synthetic peptide vaccines designed to elicit a cytotoxic T-lymphocyte response (Ochs et al., 2017, OncoImmunology). These therapies aim to exploit the high specificity of the neoantigen to achieve tumor regression while minimizing damage to healthy brain tissue. However, clinical success is challenged by the blood-brain barrier, potential HLA downregulation, and the immunosuppressive tumor microenvironment (Pishko et al., 2020, Frontiers in Oncology).

Other names

H3.3K27M-HLA-A*02:01 complexH3.3 K27M neoepitopeHLA-A2/H3.3K27MHistone H3.3 K27M mutation-derived neoantigen

Recognition of the peptide-MHC complex by specific T-cell receptors (TCRs) on cytotoxic T-lymphocytes, leading to targeted lysis of tumor cells expressing the H3.3-K27M mutation.