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Myeloid-specific KDM6B inhibition sensitizes Glioblastoma to PD1 blockade

ABSTRACT: Glioblastoma (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 specific Kdm6b deletion enhanced pro-inflammatory pathways and improved survival in GBM tumor-bearing mice. Mechanistic studies elucidated that the absence of Kdm6b enhances antigen-presentation, interferon response and phagocytosis in myeloid cells by inhibiting mediators of immune suppression including Mafb, Socs3 and Sirpa. Further, pharmacological inhibition of KDM6B mirrored the functional phenotype of Kdm6b deleted 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.

PROVIDER: EGAS00001007002 | EGA |

REPOSITORIES: EGA

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Project description:Several innate immune cell subsets have recently been identified to maintain gut homeostasis in both human and mice. Among these subsets, CX3CR1high CD11b+ CD11c+ cells contribute to intestinal tolerance through various mechanisms in mice. However, whether tolerogenic innate myeloid cells are present in the human intestine is not clearly defined. In this manuscript, we identified an intestinal myeloid cell subset possessing tolerogenic ability. HLA-DRhigh CD14+ CD163high cells in the human colon were divided into two subsets based on CD160 expression: CD163high CD160high and CD163high CD160low cells. Both cell subsets exhibited high levels of IL-10 production and high phagocytic activities. CD163high CD160high cells suppressed effector CD4+ T cell proliferation by a Foxp3+ Treg cell induction-independent mechanism. We further observed that the number and suppressive activity of these cells were profoundly decreased in patients with ulcerative colitis (UC). In addition, CD163high CD160high cells in the UC patients showed inflammatory phenotype, such as increased expression of IL6, CD80, and CD86, accompanied with decreased IL10RB expression. Our results highlight that a tolerogenic CD163high CD160high cell subset might be implicated in the prevention of UC development. Gene expression analysis of murine CX3CR1high cells (n=10) and murine blood Ly6c+ CD11b+ monocytes (n=6) were performed using Whole Mouse Genome Microarray Kit, 4x44K V2 (G4846A) as dye-swapped experiments.

2016-07-17 | E-GEOD-79628 | biostudies-arrayexpress

Microarray analysis of CD14+ CD163high CD160high cells in human intestinal lamina propria

Project description:Several innate immune cell subsets have recently been identified to maintain gut homeostasis in both human and mice. Among these subsets, CX3CR1high CD11b+ CD11c+ cells contribute to intestinal tolerance through various mechanisms in mice. However, whether tolerogenic innate myeloid cells are present in the human intestine is not clearly defined. In this manuscript, we identified an intestinal myeloid cell subset possessing tolerogenic ability. HLA-DRhigh CD14+ CD163high cells in the human colon were divided into two subsets based on CD160 expression: CD163high CD160high and CD163high CD160low cells. Both cell subsets exhibited high levels of IL-10 production and high phagocytic activities. CD163high CD160high cells suppressed effector CD4+ T cell proliferation by a Foxp3+ Treg cell induction-independent mechanism. We further observed that the number and suppressive activity of these cells were profoundly decreased in patients with ulcerative colitis (UC). In addition, CD163high CD160high cells in the UC patients showed inflammatory phenotype, such as increased expression of IL6, CD80, and CD86, accompanied with decreased IL10RB expression. Our results highlight that a tolerogenic CD163high CD160high cell subset might be implicated in the prevention of UC development. Gene expression analysis of pooled lamina propria cells (LPCs) (n=12) and human blood CD14+ monocytes (n=7) were performed using Whole Human Genome Microarray Kit, 4x44K (G4112F) as one-color experiments.

2016-07-17 | E-GEOD-79627 | biostudies-arrayexpress

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