TMIC-15. Reactive Oligodendrocytes Promote Glioblastoma Progression via CCL5/CCR5-Mediated Glioma Stem Cell Maintenance

Abstract BACKGROUND Glioblastoma (GBM) progression is tightly linked to microenvironmental interactions that remain poorly defined. Oligodendrocyte-lineage cells (OLs), traditionally viewed as passive bystanders, are increasingly recognized in the GBM niche, yet their functional role remains unexplored. METHODS Using integrated single-cell RNA sequencing, spatial transcriptomics, cytokine profiling, and functional assays across primary (newly diagnosed) and recurrent GBM samples, we investigated OL-GBM interactions. An OL meta-atlas encompassing 336,000 OL cells from 226 patients was constructed to contextualize OL phenotypes across CNS pathologies. RESULTS We found OLs are selectively recruited to the GBM tumor border via tumor-secreted CX3CL1 and infiltrate the tumor core at recurrence. Tumor-associated OLs adopt an interferon-driven reactive state, distinct from their healthy counterparts. These reactive OLs secrete pro-tumorigenic cytokines, including CCL5. We show that CCL5 supports GBM cell proliferation, particularly in recurrent GBM. Its receptor, CCR5, was selectively expressed in glioma stem-like cells (GSCs) and correlated with poor prognosis. Genetic and pharmacologic CCR5 inhibition impaired GSC viability, reduced tumor burden, and extended survival in orthotopic xenografts. CONCLUSIONS Our study identifies a previously unrecognized paracrine axis between reactive OLs and GSCs mediated by CCL5/CCR5 signalling. This axis is amplified in recurrence and represents a therapeutic vulnerability in GBM. Targeting microenvironmental contributors such as OLs may complement existing GBM therapies.