Gliomas tend to be heavily infiltrated with myeloid cells. These immune cells play a pivotal role in tumor progression and the suppression of anti-tumor immune responses. To better understand the functional role of myeloid cells in gliomas, researchers led by Ludwig Harvard’s Tyler Miller, Chadi El Farran and Bradley Bernstein—with important contributions from Jennifer Guerriero’s lab at the Harvard Center—leveraged single-cell RNA sequencing data from 85 diverse gliomas and applied new computational methods to delineate four major immunomodulatory programs found across myeloid cell types. They then explored these programs using an integrated suite of methods, including lineage tracing, spatial transcriptomics, chromatin accessibility and experiments in ex vivo models. The researchers reported in a February paper in Nature their exhaustive characterization of the gene expression programs they had identified in myeloid cells. These include microglial inflammatory and scavenger immunosuppressive programs, which are both unique to primary brain tumors; and systemic inflammatory and complement immunosuppressive programs that are also expressed by non-brain tumors. The programs are driven not by the origins of myeloid cells or tumor mutational states but by microenvironmental cues—including tumor hypoxia, interleukin-1β, TGFβ and standard-of-care dexamethasone treatment—and can predict responses to immunotherapy and overall patient survival. The team’s exhaustive characterization of mediating genomic elements, transcription factors and signaling pathways associated with each program uncovers potential strategies to manipulate glioma-associated myeloid cells to improve responses to immunotherapy.
Programs, origins and immunomodulatory functions of myeloid cells in glioma
Nature, 2025 February 26