Reactive Oligodendrocytes Influence Glioblastoma Progression via CCL5/CCR5 Signaling

Glioblastoma (GBM) evolves within a microenvironment abundant in oligodendrocyte-lineage (OL) cells. In this study, we utilized single-cell and spatial transcriptomics from primary and recurrent GBM tumors, immunohistochemistry, cytokine profiling, and migration assays to show that GBM cells recruit OLs to the tumor border via CXC3L1/CXC3R1 signaling. A pan-disease human OL meta-atlas and syngeneic mouse models reveal an interferon-induced reactive OL state, akin to those seen in demyelinating inflammatory and traumatic injury, which is enriched in CNS malignancies. These reactive OLs secrete pro-tumorigenic cytokines, notably CCL5, that promote GBM tumor cell growth through CCR5 signaling. CCR5 is preferentially expressed in glioma stem-like cells (GSCs) and upregulated at recurrence. Targeting CCR5 with genetic knockdown or FDA-approved drug Maraviroc impairs GSC stemness and prolongs survival in GBM models. Our work highlights the functional interplay between OLs and GBM cells and positions the CCL5/CCR5 axis as a druggable target in GBM. Citation Format: Nicholas Mikolajewicz, Kui Zhai, Anish Puri, Petar Miletic, Nazanin Tatari, jiarun Wei, Neil Savage, Zhi Huang, Qian Huang, Seon Yong Lee, Mahta Jan-Ahmadnejad, Roseanne Nguyen, David Chen, Tiegan Korman, Daniel Mobilio, Maxwell Topley, Jack Qinyu Lu, Matthew R. Voisin, Zsolt Zador, Shawn C. Chafe, Chitra Venugopal, Kevin R. Brown, Gelareh Zadeh, Hong Han, Julien Muffat, Shideng Bao, Sheila K. Singh, Jason Moffat. Reactive oligodendrocytes promote glioblastoma progression through CCL5/CCR5-mediated glioma stem cell maintenance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6228.