142 Arginine deprivation improves survival and activates the immune system in mouse models of diffuse midline glioma

Vollständiger Abstract

Worum geht es in dieser Arbeit?

Abstract Introduction Diffuse midline glioma (DMG) is a rare but fatal childhood brain tumour with no successful treatments. An inert immune microenvironment is a key factor in the failure to find suitable treatments. Arginine deprivation using ADI-PEG20 has been effective in treating a number of cancers, particularly those which cannot generate their own arginine. Our previous studies demonstrated that ADI-PEG20 combined with radiation eradicated GBM tumours and extended survival of animals indefinitely. ADI-PEG20 reprogrammed the tumour microenvironment in GBM and therefore may be an effective strategy in DMG. Methods In vitro: Three mouse DMG cell lines (H3.3K27M, H3.1K27M, H3WT) were grown as neurospheres, treated with ADI-PEG20 and 5 days later given radiation. Viability assays using CCK8 were performed 8 days after initial treatment. In vivo The same cell lines were intracranially injected into C57BL/6J mice. Once tumours were established, mice were treated weekly with ADI-PEG20, radiation, combination, or saline. Mice were culled when symptoms appeared and brains were harvested and analysed using spatial transcriptomics, IHC and IF. Results Treatment with ADI-PEG20 significantly reduced viability measured by CCK8 in H3.3K27M and H3WT cell lines. In vivo, ADI-PEG20 significantly increased survival compared to saline and radiation treatment in mice with H3WT tumours. Spatial transcriptomics revealed upregulation of a number of immune pathways following treatment with ADI-PEG20, and histology analysis indicated increased activation of microglial cells. Conclusions and future work ADI-PEG20 significantly affects the ability of DMG cells to grow in vitro, and increases survival in mice with H3WT tumours. It activates a number of immune pathways and microglial cells. It therefore warrants testing clinically in DMG patients, and may be effective in combination with immunotherapy.