PT  - JOURNAL ARTICLE
AU  - Sangeeta Goswami
AU  - Deblina Raychaudhuri
AU  - Pratishtha Singh
AU  - Seanu Meena Natarajan
AU  - Yulong Chen
AU  - Candice Poon
AU  - Mercedes Hennessey
AU  - Jan Zhang
AU  - Swetha Anandhan
AU  - Brittany Parker Kerrigan
AU  - Marc D. Macaluso
AU  - Zhong He
AU  - Sonali Jindal
AU  - Frederick F. Lang
AU  - Sreyashi Basu
AU  - Padmanee Sharma
TI  - Myeloid-specific KDM6B inhibition sensitizes Glioblastoma to PD1 blockade
AID  - 10.1101/2022.11.28.518243
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.11.28.518243
4099  - http://biorxiv.org/content/early/2022/11/29/2022.11.28.518243.short
4100  - http://biorxiv.org/content/early/2022/11/29/2022.11.28.518243.full
AB  - 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.Competing Interest StatementP.S. reports consulting, advisory roles, and/or stocks/ownership for Achelois, Apricity Health, BioAlta, Codiak BioSciences, Constellation, Dragonfly Therapeutics, Forty-Seven Inc., Hummingbird, ImaginAb, Jounce Therapeutics, Lava Therapeutics, Lytix Biopharma, Marker Therapeutics, BioNTx, Oncolytics, Glympse, Infinity Pharma, and Polaris and owns a patent licensed to Jounce Therapeutics.