H3K27M-specific T-cell receptor (MHC class II-restricted) (H3K27M-TCR (MHC II))

H3K27M-specific T-cell receptors (TCRs) are specialized immune receptors that recognize the lysine-to-methionine mutation at position 27 of histone H3 (H3K27M), a hallmark driver mutation in pediatric diffuse midline gliomas (DMG) (Boschert et al., 2024). While much research has focused on MHC class I-restricted TCRs, recent studies have identified TCRs that recognize H3K27M peptides presented by MHC class II molecules, such as HLA-DR and HLA-DQ (Boschert et al., 2024). These receptors are primarily expressed on CD4+ T cells and are essential for orchestrating a comprehensive anti-tumor immune response, often induced by neoantigen-specific peptide vaccines (Mueller et al., 2020). By specifically targeting the K27M neoepitope, these TCRs enable the immune system to selectively attack malignant cells while sparing healthy brain tissue, which lacks the mutation. In clinical development, these TCRs are being utilized in engineered TCR-T cell therapies and as biomarkers for monitoring the efficacy of immunotherapy in patients with DMG and diffuse intrinsic pontine glioma (DIPG) (Majzner et al., 2022). They are also being studied in combination with checkpoint inhibitors like PD-1 blockers to overcome the immunosuppressive tumor microenvironment (Daniels et al., 2022). However, their therapeutic success is often limited by the low expression of MHC molecules in the brain and the potential for severe neuroinflammation, such as obstructive hydrocephalus, following T-cell activation in the brainstem (Majzner et al., 2022). Despite these challenges, the identification of MHC class II-restricted TCRs provides a promising avenue for enhancing the durability of immune responses against H3K27M-mutant tumors.

Other names

H3K27M-reactive T-cell receptorH3.3K27M-specific TCRMHC class II-restricted H3K27M TCRH3K27M-specific CD4+ TCR

The TCR specifically recognizes the H3K27M neoantigenic peptide presented by MHC class II molecules on the surface of tumor cells or antigen-presenting cells. Upon binding, the TCR-CD3 complex initiates intracellular signaling cascades, including the activation of LCK and ZAP-70, leading to T-cell activation, proliferation, and the production of cytokines such as IFN-gamma and TNF-alpha. This response promotes an anti-tumor environment and can lead to direct or indirect destruction of H3K27M-mutant glioma cells.