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; Jian Jian Li

doi:10.1038/s41467-022-29137-3

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

Nat Commun. 2022 Mar 21;13(1):1511. doi: 10.1038/s41467-022-29137-3.

Authors

Nian Jiang^{1

2}, Bowen Xie^{1

3}, Wenwu Xiao⁴, Ming Fan¹, Shanxiu Xu⁵, Yixin Duan¹, Yamah Hamsafar⁶, Angela C Evans¹, Jie Huang¹, Weibing Zhou^{1

7}, Xuelei Lin², Ningrong Ye², Siyi Wanggou², Wen Chen^{1

7}, Di Jing^{4

7}, Ruben C Fragoso^{1

8}, Brittany N Dugger⁶, Paul F Wilson^{1

8}, Matthew A Coleman^{1

8}, Shuli Xia⁹, Xuejun Li^{2

10}, Lun-Quan Sun¹¹, Arta M Monjazeb^{1

8}, Aijun Wang⁵, William J Murphy^{8

12}, Hsing-Jien Kung^{4

13}, Kit S Lam^{4

8}, Hong-Wu Chen^{4

8

14}, Jian Jian Li^{15

16}

Affiliations

¹ Department of Radiation Oncology, University of California Davis School of Medicine, Sacramento, CA, 95817, USA.
² Department of Neurosurgery, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, PR China.
³ Institute for Immunology and School of Medicine, Tsinghua University, Beijing, 100084, PR China.
⁴ Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, CA, 95817, USA.
⁵ Department of Surgery, School of Medicine, University of California Davis, Sacramento, CA, 95817, USA.
⁶ Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA, 95817, USA.
⁷ Department of Radiation Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, PR China.
⁸ NCI-Designated Comprehensive Cancer Center, University of California Davis, Sacramento, CA, 95817, USA.
⁹ Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA.
¹⁰ Hunan International Scientific and Technological Cooperation Base of Brain Tumor Research, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, PR China.
¹¹ Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, PR China.
¹² Departments of Dermatology and Internal Medicine, UC Davis School of Medicine, Sacramento, CA, 95817, USA.
¹³ TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, 110, Taiwan.
¹⁴ Veterans Affairs Northern California Health Care System, Mather, CA95655, USA.
¹⁵ Department of Radiation Oncology, University of California Davis School of Medicine, Sacramento, CA, 95817, USA. jijli@ucdavis.edu.
¹⁶ NCI-Designated Comprehensive Cancer Center, University of California Davis, Sacramento, CA, 95817, USA. jijli@ucdavis.edu.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
CD47 Antigen* / metabolism
Cell Line, Tumor
Fatty Acids
Glioblastoma* / genetics
Glioblastoma* / radiotherapy
Humans
Immune Evasion
Mice
Phagocytosis

Substances

CD47 Antigen
CD47 protein, human
Fatty Acids

Abstract

Publication types

MeSH terms

Substances

Grants and funding