Abstract A060: Reactive oligodendrocytes promote glioblastoma progression through CCL5/CCR5-mediated glioma stem cell maintenance

Abstract Glioblastoma (GBM) thrives in an ecosystem that is shaped by intricate intercellular interactions that contribute to tumor progression and treatment resistance. Recent studies have shown that the oligodendrocyte lineage (OL) is abundantly enriched in the GBM tumor microenvironment. In this study, we utilized single-cell RNA sequencing (scRNA-seq) profiles from 120 primary and recurrent GBM tumors, spatial transcriptomics, immunohistochemistry, cytokine profiling, and in vitro migration assays to demonstrate that OLs are selectively recruited to the GBM tumor border, and subsequently incorporated into the tumor mass at recurrence. Using a pan-disease single-cell human OL meta-atlas, we identified a population of malignancy-associated reactive OLs, akin to those seen in demyelinating inflammatory and traumatic conditions. The interferon-mediated induction of this population was validated using in vivo GL261 and CT2A syngeneic mouse models. Cytokine profiling and ligand-receptor (LR) interaction analyses identified several pro-tumorigenic cytokines secreted by reactive OLs, including CCL5. Moreover, we found that CCR5, the CCL5 receptor, was preferentially expressed in glioma stem-like cells (GSCs) and upregulated at recurrence. Targeting CCR5 in GBM tumor cells with genetic knockdown or pharmacological inhibition impaired GSC stemness and prolonged the survival of mice bearing GBM tumors. Our work highlights the functional interplay between OLs and GBM cells and positions the CCL5/CCR5 axis as a druggable target for GBM. Citation Format: Jason Moffat. Reactive oligodendrocytes promote glioblastoma progression through CCL5/CCR5-mediated glioma stem cell maintenance [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A060.