ID #898 Dordaviprone (ONC201) reverses T-cell sequestration in diffuse midline glioma models.

Abstract

Diffuse midline glioma (DMG) is a highly aggressive paediatric and adolescent brain tumour arising in the midline structures of the central nervous system. DMG exhibit a cold tumour immune microenvironment (TIME) characterised by low levels of infiltrating T-cells, limiting anti-tumour adaptive response. Dordaviprone (ONC201) is a DRD2 antagonist/ClpP agonist that recently received accelerated FDA-approval for progressive H3K27M-mutant DMG. Emerging evidence from our group shows that dordaviprone enhances T-cell infiltration into the TIME of DMG models, however the mechanisms underlying this phenomenon remain enigmatic. Given findings in glioblastoma, where T-cell sequestration in the bone marrow (BM) results from impaired surface expression of spingosine-1-phosphate receptor 1 (S1PR1), we investigated whether a similar mechanism contributes to systemic immune dysregulation in DMG, and whether dordaviprone can influence T-cell egress

Single-cell transcriptomic analysis of BM from immunocompetent DMG-PPK mice (PdgfraD842V, Trp53DN, H3f3aK27M mutations) revealed a higher proportion of T-cells in the DMG sample compared to sham-engrafted (HBSS) and tumour-naïve controls, representative of T-cell sequestration, potentially contributing to the lack of T-cells within the TIME. Acute treatment of dordaviprone (125 mg/kg) significantly reduced T-cells within the BM, indicative of T-cell egress, also seen via flow cytometry. Furthermore, flow cytometry demonstrated an increased proportion of S1PR1+ T-cells in the BM following dordaviprone treatment (log2FC = 0.73, P = 0.001), however, no significant changes were detected between sham and vehicle groups. These findings suggest an alternative mechanism behind T-cell sequestration in DMG models, while indicating that dordaviprone potentially restores T-cell egress by increasing S1PR1 surface expression.

In conclusion, DMG mouse models exhibit T-cell sequestration within the BM, reversed by dordaviprone. Our results support a model where dordaviprone promotes T-cell infiltration by releasing lymphocytes from the BM, warranting further investigation into the mechanisms driving sequestration and the functional phenotypes of circulating and infiltrative T-cells in DMG.