Myeloid-specific KDM6B inhibition sensitizes Glioblastoma to PD1 blockade

Abstract

AbstractGlioblastoma (GBM) tumors are enriched in immune-suppressive myeloid cells and are refractory to immune checkpoint therapy (ICT). Targeting epigenetic pathways to reprogram the functional phenotype of immune-suppressive myeloid cells to overcome resistance to ICT remains unexplored. Single-cell and spatial transcriptomic analyses of human GBM tumors demonstrated high expression of an epigenetic enzyme - histone 3 lysine 27 demethylase (KDM6B) in intra- tumoral immune-suppressive myeloid cell subsets. Importantly, myeloid-cell specificKdm6bdeletion enhanced pro-inflammatory pathways and improved survival in GBM tumor-bearing mice. Mechanistic studies elucidated that the absence ofKdm6benhances antigen-presentation, interferon response and phagocytosis in myeloid cells by inhibiting mediators of immune suppression includingMafb, Socs3andSirpa. Further, pharmacological inhibition of KDM6B mirrored the functional phenotype ofKdm6bdeleted myeloid cells and enhanced anti-PD1 efficacy. Thus, this study identified KDM6B as an epigenetic regulator of the functional phenotype of myeloid cell subsets and a potential therapeutic target to improve response to ICT.