An immunosuppressive vascular niche drives macrophage polarization and immunotherapy resistance in glioblastoma

Cancer immunity is subjected to spatiotemporal regulation by leukocyte interaction with neoplastic and stromal cells, contributing to immune evasion and immunotherapy resistance. Here, we identify a distinct mesenchymal-like population of endothelial cells (ECs) that form an immunosuppressive vascul...

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Bibliographic Details
Published in:Science advances 2024-03, Vol.10 (9), p.eadj4678-eadj4678
Main Authors: Yang, Fan, Akhtar, Md Naushad, Zhang, Duo, El-Mayta, Rakan, Shin, Junyoung, Dorsey, Jay F, Zhang, Lin, Xu, Xiaowei, Guo, Wei, Bagley, Stephen J, Fuchs, Serge Y, Koumenis, Constantinos, Lathia, Justin D, Mitchell, Michael J, Gong, Yanqing, Fan, Yi
Format: Article
Language:English
Subjects:
Animals
Biomedicine and Life Sciences
Brain Neoplasms - genetics
Cell Line, Tumor
Endothelial Cells - pathology
Glioblastoma - genetics
Immunology
Immunosuppression Therapy
Macrophages
Mice
SciAdv r-articles
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Summary:Cancer immunity is subjected to spatiotemporal regulation by leukocyte interaction with neoplastic and stromal cells, contributing to immune evasion and immunotherapy resistance. Here, we identify a distinct mesenchymal-like population of endothelial cells (ECs) that form an immunosuppressive vascular niche in glioblastoma (GBM). We reveal a spatially restricted, Twist1/SATB1-mediated sequential transcriptional activation mechanism, through which tumor ECs produce osteopontin to promote immunosuppressive macrophage (Mφ) phenotypes. Genetic or pharmacological ablation of Twist1 reverses Mφ-mediated immunosuppression and enhances T cell infiltration and activation, leading to reduced GBM growth and extended mouse survival, and sensitizing tumor to chimeric antigen receptor T immunotherapy. Thus, these findings uncover a spatially restricted mechanism controlling tumor immunity and suggest that targeting endothelial Twist1 may offer attractive opportunities for optimizing cancer immunotherapy.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.adj4678