Major histocompatibility complex class II–Histone H3K27M peptide complex (MHC II–H3K27M)

The MHC class II–H3K27M peptide complex is a tumor-specific neoantigen formed by the presentation of a mutated histone H3 fragment on the cell surface via Major Histocompatibility Complex (MHC) class II molecules. The H3K27M mutation, characterized by a lysine-to-methionine substitution at position 27, is a hallmark driver mutation found in over 80% of diffuse midline gliomas (DMGs), including diffuse intrinsic pontine glioma (DIPG) (Ochs et al., 2017, J Clin Invest). This complex is specifically recognized by the T-cell receptors (TCRs) of CD4+ helper T cells, which are essential for orchestrating a sustained anti-tumor immune response (Chheda et al., 2018, J Exp Med). Because the H3K27M mutation is highly specific to malignant cells and absent in healthy tissue, the MHC II–H3K27M complex serves as a high-priority target for precision immunotherapies, such as peptide-based vaccines and TCR-engineered T-cell therapies (Mueller et al., 2020, Nature Communications). Current therapeutic strategies often focus on patients carrying the HLA-DRB1*01:01 allele, which has been identified as the primary MHC II molecule capable of presenting the H3K27M neoepitope to the immune system (Okada et al., 2019, Cancer Cell). Targeting this complex aims to overcome the immunosuppressive environment of pediatric brain tumors by recruiting specialized immune cells to selectively eliminate glioma cells while sparing normal brain tissue.

Other names

HLA-DR–H3K27M complexH3.3K27M–MHC II complexHistone H3.3 K27M mutation-derived neoantigenH3K27M-HLA-DRB1*01:01 complex

Induction of antigen-specific CD4+ T cell responses through the recognition of the H3K27M neoepitope presented by MHC class II molecules, leading to anti-tumor cytokine production and recruitment of cytotoxic immune cells.