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 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:10 |
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| Enthalten in: |
Science advances - 10(2024), 9 vom: 28. März, Seite eadj4678 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Yang, Fan [VerfasserIn] |
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| Themen: |
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| Anmerkungen: |
Date Completed 01.03.2024 Date Revised 16.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1126/sciadv.adj4678 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM369067487 |
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| 245 | 1 | 3 | |a An immunosuppressive vascular niche drives macrophage polarization and immunotherapy resistance in glioblastoma |
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| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 700 | 1 | |a Akhtar, Md Naushad |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Duo |e verfasserin |4 aut | |
| 700 | 1 | |a El-Mayta, Rakan |e verfasserin |4 aut | |
| 700 | 1 | |a Shin, Junyoung |e verfasserin |4 aut | |
| 700 | 1 | |a Dorsey, Jay F |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Lin |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Xiaowei |e verfasserin |4 aut | |
| 700 | 1 | |a Guo, Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Bagley, Stephen J |e verfasserin |4 aut | |
| 700 | 1 | |a Fuchs, Serge Y |e verfasserin |4 aut | |
| 700 | 1 | |a Koumenis, Constantinos |e verfasserin |4 aut | |
| 700 | 1 | |a Lathia, Justin D |e verfasserin |4 aut | |
| 700 | 1 | |a Mitchell, Michael J |e verfasserin |4 aut | |
| 700 | 1 | |a Gong, Yanqing |e verfasserin |4 aut | |
| 700 | 1 | |a Fan, Yi |e verfasserin |4 aut | |
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