@article{03cb1e42c1ec4ab889e0c8d2f3347f76,
title = "Fatty acid oxidation fuels glioblastoma radioresistance with CD47-mediated immune evasion",
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.",
author = "Nian Jiang and Bowen Xie and Wenwu Xiao and Ming Fan and Shanxiu Xu and Yixin Duan and Yamah Hamsafar and Evans, {Angela C.} and Jie Huang and Weibing Zhou and Xuelei Lin and Ningrong Ye and Siyi Wanggou and Wen Chen and Di Jing and Fragoso, {Ruben C.} and Dugger, {Brittany N.} and Wilson, {Paul F.} and Coleman, {Matthew A.} and Shuli Xia and Xuejun Li and Sun, {Lun Quan} and Monjazeb, {Arta M.} and Aijun Wang and Murphy, {William J.} and Kung, {Hsing Jien} and Lam, {Kit S.} and Chen, {Hong Wu} and Li, {Jian Jian}",
note = "Funding Information: We acknowledge Dr. Irving Weissman for providing the anti-human CD47 antibody Hu5F9-G4, Dr. William Frazier for providing anti-mouse CD47 MIAP301 hybridoma, Dr. Watkins Vockley for providing anti-ACAD9 antibody, Dr. Orin Bloch for discussion of in vivo mouse GBM model, and Dr. Ji Ming Wang for reading the manuscript. The clinical and pathological studies conducted in Xiangya Hospital, Central South University, were supported by the National Foundation of Natural Science (81672509). Dr. Nian Jiang was supported by China Scholarship Council (201706370117). The radioresistant GBM cell lines and in vitro and in vivo studies using radioresistant mouse GBM cells carried out at the Cancer Center of University of California Davis were supported by NCI RO1 CA213830 (J.J.L.), NCI R01 CA224900 (H.-W.C.), VA MERIT Award I01BX004271 (H.-W.C.), UC Davis Immunology Pilot Grant Support (J.J.L.), and UC Davis Cancer Center supported by the CCSG Grant awarded by the National Cancer Institute (Dr. Primo Lara; NCI P30CA093373). This work is dedicated to the memory of Dr. William C. Dewey for his mentoring and long-term friendship. “A mentor is someone who sees more talent and ability within you, than you see in yourself, and helps bring it out of you”—Bob Proctor. Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = dec,
doi = "10.1038/s41467-022-29137-3",
language = "English",
volume = "13",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Research",
number = "1",
}