Fatty acid oxidation fuels glioblastoma radioresistance with CD47-mediated immune evasion

Nian Jiang, Bowen Xie, Wenwu Xiao, Ming Fan, Shanxiu Xu, Yixin Duan, Yamah Hamsafar, Angela C. Evans, Jie Huang, Weibing Zhou, Xuelei Lin, Ningrong Ye, Siyi Wanggou, Wen Chen, Di Jing, Ruben C. Fragoso, Brittany N. Dugger, Paul F. Wilson, Matthew A. Coleman, Shuli Xia, Xuejun Li, Lun-Quan Sun, Arta M. Monjazeb, Aijun Wang, William J. Murphy, Hsing-Jien Kung, Kit S. Lam, Hong-Wu Chen and Jian Jian Li ()
Additional contact information
Nian Jiang: University of California Davis School of Medicine
Bowen Xie: University of California Davis School of Medicine
Wenwu Xiao: University of California Davis
Ming Fan: University of California Davis School of Medicine
Shanxiu Xu: University of California Davis
Yixin Duan: University of California Davis School of Medicine
Yamah Hamsafar: University of California Davis
Angela C. Evans: University of California Davis School of Medicine
Jie Huang: University of California Davis School of Medicine
Weibing Zhou: University of California Davis School of Medicine
Xuelei Lin: Central South University
Ningrong Ye: Central South University
Siyi Wanggou: Central South University
Wen Chen: University of California Davis School of Medicine
Di Jing: University of California Davis
Ruben C. Fragoso: University of California Davis School of Medicine
Brittany N. Dugger: University of California Davis
Paul F. Wilson: University of California Davis School of Medicine
Matthew A. Coleman: University of California Davis School of Medicine
Shuli Xia: Johns Hopkins School of Medicine
Xuejun Li: Central South University
Lun-Quan Sun: Central South University
Arta M. Monjazeb: University of California Davis School of Medicine
Aijun Wang: University of California Davis
William J. Murphy: University of California Davis
Hsing-Jien Kung: University of California Davis
Kit S. Lam: University of California Davis
Hong-Wu Chen: University of California Davis
Jian Jian Li: University of California Davis School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: Abstract Glioblastoma multiforme (GBM) remains the top challenge to radiotherapy with only 25% one-year survival after diagnosis. Here, we reveal that co-enhancement of mitochondrial fatty acid oxidation (FAO) enzymes (CPT1A, CPT2 and ACAD9) and immune checkpoint CD47 is dominant in recurrent GBM patients with poor prognosis. A glycolysis-to-FAO metabolic rewiring is associated with CD47 anti-phagocytosis in radioresistant GBM cells and regrown GBM after radiation in syngeneic mice. Inhibition of FAO by CPT1 inhibitor etomoxir or CRISPR-generated CPT1A−/−, CPT2−/−, ACAD9−/− cells demonstrate that FAO-derived acetyl-CoA upregulates CD47 transcription via NF-κB/RelA acetylation. Blocking FAO impairs tumor growth and reduces CD47 anti-phagocytosis. Etomoxir combined with anti-CD47 antibody synergizes radiation control of regrown tumors with boosted macrophage phagocytosis. These results demonstrate that enhanced fat acid metabolism promotes aggressive growth of GBM with CD47-mediated immune evasion. The FAO-CD47 axis may be targeted to improve GBM control by eliminating the radioresistant phagocytosis-proofing tumor cells in GBM radioimmunotherapy.

Date: 2022
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Citations: View citations in EconPapers (3)

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DOI: 10.1038/s41467-022-29137-3

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