H3K27M diffuse midline glioma is homologous recombination defective and sensitized to radiotherapy and NK cell-mediated antitumor immunity by PARP inhibition

Apr 10, 2025Neuro-oncology

A common childhood brain tumor has DNA repair problems and becomes more sensitive to radiotherapy and immune cell attack when treated with PARP inhibitors

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Abstract

The H3K27M mutation in diffuse midline glioma is associated with a homologous recombination repair defect.

This mutation leads to impaired repair processes following radiation treatment.
H3K27M DMG cells showed increased sensitivity to the PARP inhibitor olaparib compared to isogenic controls.
Olaparib treatment combined with radiation therapy resulted in an innate immune response and enhanced NK cell activation.
In immunocompetent mice, both olaparib and a selective PARP inhibitor increased NK cell activity against DMG tumors.
The findings suggest a potential therapeutic strategy that leverages the HRR deficiency in H3K27M DMG.

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BACKGROUND: Radiotherapy (RT) is the primary treatment for diffuse midline glioma (DMG), a lethal pediatric malignancy defined by histone H3 lysine 27-to-methionine (H3K27M) mutation. Based on the loss of H3K27 trimethylation producing broad epigenomic alterations, we hypothesized that H3K27M causes a functional double-strand break (DSB) repair defect that could be leveraged therapeutically with PARP inhibitor and RT for selective radiosensitization and antitumor immune response.

METHODS: H3K27M isogenic DMG cells and orthotopic brainstem DMG tumors in immune deficient and syngeneic, immune competent mice were used to evaluate the efficacy and mechanisms of PARP1/2 inhibition by olaparib or PARP1-selective inhibition by AZD9574 with concurrent RT.

RESULTS: H3K27M mutation caused a homologous recombination repair (HRR) defect characterized by impaired RT-induced K63-linked polyubiquitination of histone H1 and inhibition of HRR protein recruitment. H3K27M DMG cells were selectively radiosensitized by olaparib in comparison to isogenic controls, and this effect translated to efficacy in H3K27M orthotopic brainstem tumors. Olaparib and RT induced an innate immune response and induction of NK cell (NKG2D) activating ligands leading to increased NK cell-mediated lysis of DMG cells. In immunocompetent syngeneic orthotopic DMG tumors, either olaparib or AZD9574 in combination with RT enhanced intratumoral NK cell infiltration and activity in association with NK cell-mediated therapeutic responses and favorable activity of AZD9574.

CONCLUSIONS: The HRR deficiency in H3K27M DMG can be therapeutically leveraged with PARP inhibitors to radiosensitize and induce an NK cell-mediated antitumor immune response selectively in H3K27M DMG, supporting the clinical investigation of PARP1 inhibitors with RT in DMG patients.

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H3K27M diffuse midline glioma is homologous recombination defective and sensitized to radiotherapy and NK cell-mediated antitumor immunity by PARP inhibition

Abstract

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