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Programs, Origins, and Niches of Immunomodulatory Myeloid Cells in Human Gliomas - Single Cell Portal
Gliomas are incurable malignancies notable for an immunosuppressive microenvironment with abundant myeloid cells whose immunomodulatory properties remain poorly defined. Here, utilizing scRNA-seq data for Glioma primary tumors from 85 human tumors, we extracted 183,062 myeloid cells and discovered that nearly all glioma-associated myeloid cells express at least one of four immunomodulatory activity programs. These include a Scavenger Immunosuppressive program, a Complement Immunosuppressive program, a Microglial Inflammatory program, and a Systemic inflammatory program. Integration of mitochondrial DNA-based lineage tracing, spatial transcriptomics, and functional organoid models reveals that these programs are driven by microenvironmental cues and therapies rather than myeloid cell type or origin. All four programs are present in lower-grade and high-grade gliomas and expressed in multiple myeloid cell types derived from blood or resident myeloid cell origins. The Scavenger Immunosuppressive program is induced in hypoxic regions, while the Complement Immunosuppressive program is driven by dexamethasone. Both immunosuppressive programs are less prevalent in lower-grade gliomas, which are instead enriched for the Microglial Inflammatory program. We validated this striking myeloid cell plasticity by demonstrating that application of peripheral blood monocytes to glioma organoid models leads to de novo induction of microglia, macrophage and dendritic cell identities, and all four immunomodulatory programs. Our study provides a resource and new framework to understand immunomodulatory myeloid cells in glioma, and a foundation to develop effective immunotherapy strategies for glioma patients.
