Abhishek Dubey, Erika Yamashita, Biljana Stangeland, Imane Abbas, David Fooksman, Robert A. Harris, Gregory M. Palmer, Wade Koba, Jinghang Zhang, Benjamin Himes, Olivia R. Lu, Winson S. Ho, Raoul Kuiper, Derek M. Huffman, Zhigang Wu, Yutaka Uchida, Masaru Ishii, Rachel L. Welch, Alexander F. Fiedler, D. John M. Reynolds, Sayied Abdol Mohieb Hosainey, Kostantin Dobrenis, Qinyong Ye, Kevin Fisher, Nathaniel J. Killian, E. Richard Stanley, Emad N. Eskandar, Jinan Behnan
The skull marrow niche has recently been identified as a reservoir that supplies the brain with monocytes and neutrophils in the context of disease and injury, but its role in brain cancers remains unknown. Here we show that glioblastoma, the most malignant type of brain tumor, induces calvarial bone abnormalities in murine models and patients with glioblastoma, altering osteoclast activities and increasing the number of skull channels in mice. Single-cell RNA sequencing revealed glioblastoma-mediated alterations in the immune landscape of skull marrow and femoral bone marrow, including expansion of neutrophils and deterioration of various B cell subsets. In vivo inhibition of bone resorption reduced bone abnormalities, but promoted tumor progression in mesenchymal subtype tumors. This also abolished the survival benefit of the checkpoint inhibitor anti-PD-L1, by reducing activated T cell and increasing inflammatory neutrophil numbers. Together, these data provide insight into how brain tumors affect skull bone and the immune environment.