Using single-cell and spatial transcriptomics, Goswami et al. identified selective expression of KDM6B in immune-suppressive myeloid cell subsets in GBM patients, and demonstrated its role as an epigenetic regulator of intratumoral myeloid cell function. Genetic deletion of KDM6B in myeloid cells upregulated proinflammatory gene expression, phagocytosis, and antigen presentation, and improved survival compared with controls in murine models of GBM. Pharmacological inhibition of KDM6B recapitulated the functional phenotype of KDM6B-deleted myeloid cells, and improved overall survival and sensitivity to anti-PD-1 therapy.
Contributed by Shishir Pant
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 intratumoral immune-suppressive myeloid cell subsets. Importantly, myeloid cell-specific Kdm6b deletion enhanced proinflammatory pathways and improved survival in GBM tumor-bearing mice. Mechanistic studies showed that the absence of Kdm6b enhances antigen presentation, interferon response and phagocytosis in myeloid cells by inhibition of 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. This study thus identified KDM6B as an epigenetic regulator of the functional phenotype of myeloid cell subsets and a potential therapeutic target for enhanced response to ICT.
Author Info: (1) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. sgoswami@mdanderson.org. Department of Genitourinary Medical Oncology, The Univer
Author Info: (1) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. sgoswami@mdanderson.org. Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. sgoswami@mdanderson.org. James P. Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. sgoswami@mdanderson.org. (2) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (3) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (4) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (5) Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (6) Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (7) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (8) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (9) Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (10) Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (11) Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (12) Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (13) Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (14) Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (15) Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (16) Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (17) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. padsharma@mdanderson.org. Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. padsharma@mdanderson.org. James P. Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. padsharma@mdanderson.org. Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. padsharma@mdanderson.org.
