Major histocompatibility complex class II (MHC II) presenting histone H3.3 K27M peptide (MHC II-H3K27M)

Major histocompatibility complex (MHC) class II molecules presenting the H3K27M peptide represent a specific neoantigen target found in diffuse midline gliomas (DMG) (Ochs et al., Nature, 2017). The H3K27M mutation, involving a lysine-to-methionine substitution at position 27 of histone H3.3 or H3.1, is a driver mutation in these aggressive pediatric brain tumors (Chheda et al., Nature, 2018). When this mutant peptide is processed and presented on the cell surface by MHC class II molecules, particularly HLA-DRB1*01:01, it becomes visible to CD4+ T cells (Mueller et al., Journal of Clinical Oncology, 2020). This complex is a primary target for immunotherapeutic strategies such as peptide-based vaccines (e.g., PEP-H3.3K27M) and T cell receptor (TCR) engineered T cell therapies (Kilburn et al., Neuro-Oncology, 2021). By targeting this specific neoantigen, these therapies aim to induce a robust anti-tumor immune response while sparing healthy tissues that lack the mutation. Clinical trials are currently evaluating the safety and efficacy of targeting this complex to improve outcomes in patients with H3K27M-mutant gliomas (NCT02960230).

Other names

HLA-DR-H3K27M complexH3.3K27M neoantigen-MHC II complexHistone H3.3 K27M peptide-HLA-DR complexH3K27M-HLA-DRB1*01:01

The target acts as a neoantigen complex recognized by specific T cell receptors (TCRs) on CD4+ T lymphocytes. Binding of the TCR to the H3K27M-MHC II complex triggers T cell activation, cytokine production, and a coordinated immune response against H3K27M-mutant tumor cells (Ochs et al., Nature, 2017; Chheda et al., Nature, 2018).