Programs, Origins, and Niches of Immunomodulatory Myeloid Cells in Gliomas

Abstract

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 183,062 myeloid cells from 85 human tumors, we discover that nearly all glioma-associated myeloid cells express at least one of four immunomodulatory activity programs: Scavenger Immunosuppressive, C1Q Immunosuppressive, CXCR4 Inflammatory, and IL1B Inflammatory. All four programs are present in IDH1 mutant and wild-type gliomas and are expressed in macrophages, monocytes, and microglia whether of blood or resident myeloid cell origins. Integrating our scRNA-seq data with mitochondrial DNA-based lineage tracing, spatial transcriptomics, and organoid explant systems that model peripheral monocyte infiltration, we show that these programs are driven by microenvironmental cues and therapies rather than myeloid cell type, origin, or mutation status. The C1Q Immunosuppressive program is driven by routinely administered dexamethasone. The Scavenger Immunosuppressive program includes ligands with established roles in T-cell suppression, is induced in hypoxic regions, and is associated with immunotherapy resistance. Both immunosuppressive programs are less prevalent in lower-grade gliomas, which are instead enriched for the CXCR4 Inflammatory program. Our study provides a framework to understand immunomodulatory myeloid cells in glioma, and a foundation to develop more effective immunotherapies.

Single-nucleus and spatial landscape of the sub-ventricular zone in human glioblastoma

“…While IL-1β is among the most-well characterized inflammatory cytokines in GBM, TAMs secreting IL-1β support tumor growth [51][52][53][54][55][56][57][58] , and microglia (among other cell types) are enriched in an IL-1β inflammatory program 74 , it is still unknown whether TAMs secrete Wnt-5a and if a Wnt-5a-mediated crosstalk exists between TAMs and tumor cells. However, in addition to the known pro-migration and pro-invasion functions of Wnt-5a [59][60][61][62][63] , it has been reported that the expression of Wnt-5a in human glioma is positively correlated with the presence of TAMs 64 .…”

Glioma–Immune Cell Crosstalk in Tumor Progression

“…In this regard, it is important to note that the reciprocal interactions between glioma cells and the TME are continuously evolving from tumor initiation to progression and recurrence [188,189]. While the specific mechanisms underlying the evolution of glioma tumors remain to be solved, spatial transcriptomic and proteomic evidence has shown that glioma cells are dynamically reorganized into distinct regions that display unique molecular profiles or lineage states (e.g., proneural, mesenchymal, and classical) and are constantly adapting to evolving stresses from the surrounding TME [58,190]. Thus, the characterization of gliomas in patients cannot be a singular event and requires multiple regions and time points to be analyzed.…”