Programs, Origins and Immunomodulatory Functions of Myeloid Cells in Glioma

Gliomas are incurable malignancies notable for having an immunosuppressive microenvironment with abundant myeloid cells, the immunomodulatory phenotypes of which remain poorly defined. Here we systematically investigate these phenotypes by integrating single-cell RNA sequencing, chromatin accessibility, spatial transcriptomics and glioma organoid explant systems. We discovered four immunomodulatory expression programs: microglial inflammatory and scavenger immunosuppressive programs, which are both unique to primary brain tumours, and systemic inflammatory and complement immunosuppressive programs, which are also expressed by non-brain tumours. The programs are not contingent on myeloid cell type, developmental origin or tumour mutational state, but instead are driven by microenvironmental cues, including tumour hypoxia, interleukin-1β, TGFβ and standard-of-care dexamethasone treatment. Their relative expression can predict immunotherapy response and overall survival. By associating the respective programs with mediating genomic elements, transcription factors and signalling pathways, we uncover strategies for manipulating myeloid-cell phenotypes. Our study provides a framework to understand immunomodulation by myeloid cells in glioma and a foundation for the development of more-effective immunotherapies.