Fatty acid oxidation fuels glioblastoma radioresistance with CD47-mediated immune evasion.
Fatty acid oxidation fuels glioblastoma radioresistance with CD47-mediated immune evasion.
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DOI：
10.1038/s41467-022-29137-3
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发表时间：
2022-03-21
影响因子：
16.6
通讯作者：
Li JJ
中科院分区：
文献类型：
--
作者：
Jiang N;Xie B;Xiao W;Fan M;Xu S;Duan Y;Hamsafar Y;Evans AC;Huang J;Zhou W;Lin X;Ye N;Wanggou S;Chen W;Jing D;Fragoso RC;Dugger BN;Wilson PF;Coleman MA;Xia S;Li X;Sun LQ;Monjazeb AM;Wang A;Murphy WJ;Kung HJ;Lam KS;Chen HW;Li JJ
多形性胶质母细胞瘤(GBM)仍然是放射治疗的最大挑战，确诊后仅有25%的一年存活率。在这里，我们揭示了线粒体脂肪酸氧化(FAO)酶(CPT1A、CPT2和ACAD9)和免疫检查点CD47的共同增强在复发的GBM患者中占主导地位，且预后较差。糖酵解到FAO的代谢重排与CD47在抗辐射的GBM细胞中的抗吞噬作用和同基因小鼠辐射后GBM的再生有关。用CPT1抑制剂依托莫昔尔或CRISPR诱导的CPT1a−/−、CPT2−/−、ACAD9−/−细胞对粮农组织的抑制表明，粮农组织衍生的乙酰辅酶A通过NF-κB/RELA乙酰化上调CD47的转录。阻断FAO会损害肿瘤生长，并降低CD47的抗吞噬作用。依托莫昔单抗联合抗CD47抗体通过增强巨噬细胞吞噬功能协同放射控制肿瘤再生。这些结果表明，增强的脂肪酸代谢通过CD47介导的免疫逃避促进了GBM的侵袭性生长。在GBM放射免疫治疗中，FAO-CD47轴可能通过消除抗放射吞噬的肿瘤细胞来改善GBM的控制。获得性放射抵抗是治疗胶质母细胞瘤的一个挑战。在这里，作者表明，抗辐射的胶质母细胞瘤促进线粒体脂肪酸氧化，促进细胞增殖，并通过CD47介导的抗吞噬作用诱导免疫抑制。依托莫昔单抗联合抗CD47抗体抑制FAO使胶质母细胞瘤对放射治疗增敏。
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. Acquired radioresistance is a challenge for the cure of glioblastoma. Here, the authors show that radioresistant glioblastoma boosts mitochondrial fatty acid oxidation that fuels cell proliferation and induces immunosuppression via CD47 mediated anti-phagocytosis. Inhibition of FAO by etomoxir combined with anti-CD47 antibodies sensitizes glioblastoma to radiotherapy.
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影响因子：
50.3
作者：
Chen, Ruihuan;Nishimura, Merry C.;Phillips, Heidi S.
通讯作者：
Phillips, Heidi S.
影响因子：
30.5
作者：
Han, Chuanhui;Liu, Zhida;Fu, Yang-Xin
通讯作者：
Fu, Yang-Xin
影响因子：
11.2
作者：
Candas D;Lu CL;Fan M;Chuang FY;Sweeney C;Borowsky AD;Li JJ
通讯作者：
Li JJ
影响因子：
5.3
作者：
Dubois LG;Campanati L;Righy C;D'Andrea-Meira I;Spohr TC;Porto-Carreiro I;Pereira CM;Balça-Silva J;Kahn SA;DosSantos MF;Oliveira Mde A;Ximenes-da-Silva A;Lopes MC;Faveret E;Gasparetto EL;Moura-Neto V
通讯作者：
Moura-Neto V
影响因子：
4.7
作者：
Gupta, Kshama;Vuckovic, Ivan;Burns, Terry C.
通讯作者：
Burns, Terry C.