Metabolic rewiring of macrophages by CpG potentiates clearance of cancer cells and overcomes tumor-expressed CD47-mediated 'don't-eat-me' signal
Metabolic rewiring of macrophages by CpG potentiates clearance of cancer cells and overcomes tumor-expressed CD47-mediated 'don't-eat-me' signal
复制标题
DOI：
10.1038/s41590-018-0292-y
复制
发表时间：
2019-03-01
影响因子：
30.5
通讯作者：
Beatty, Gregory L.
中科院分区：
文献类型：
--
作者：
Liu, Mingen;O'Connor, Roddy S.;Beatty, Gregory L.
巨噬细胞通过吞噬和杀伤肿瘤细胞来增强抗肿瘤免疫。虽然这些功能是由刺激和抑制信号的平衡决定的，但巨噬细胞代谢的作用尚不清楚。在这里，我们研究了巨噬细胞规避CD47介导的癌细胞抑制活性的能力。我们发现，用CpG寡脱氧核苷酸（一种Toll样受体9激动剂）刺激，引起巨噬细胞中心碳代谢的变化，使其具有抗肿瘤活性，包括吞噬CD47（+）癌细胞。CpG活化产生代谢状态，其需要脂肪酸氧化和三羧酸循环中间体的分流用于从头脂质生物合成。这种代谢输入的整合是由肉毒碱棕榈酰转移酶1A和腺苷三磷酸柠檬酸裂解酶支持的，它们一起赋予巨噬细胞能够克服癌细胞上的抑制性CD47的抗肿瘤潜力。我们的研究结果确定中央碳代谢是一个新的决定因素和潜在的治疗靶点刺激巨噬细胞的抗肿瘤活性。
Macrophages enforce antitumor immunity by engulfing and killing tumor cells. Although these functions are determined by a balance of stimulatory and inhibitory signals, the role of macrophage metabolism is unknown. Here, we study the capacity of macrophages to circumvent inhibitory activity mediated by CD47 on cancer cells. We show that stimulation with a CpG oligodeoxynucleotide, a Toll-like receptor 9 agonist, evokes changes in the central carbon metabolism of macrophages that enable anti-tumor activity, including engulfment of CD47(+) cancer cells. CpG activation engenders a metabolic state that requires fatty acid oxidation and shunting of tricarboxylic acid cycle intermediates for de novo lipid biosynthesis. This integration of metabolic inputs is underpinned by carnitine palmitoyltransferase 1A and adenosine tri-phosphate citrate lyase, which, together, impart macrophages with antitumor potential capable of overcoming inhibitory CD47 on cancer cells. Our findings identify central carbon metabolism to be a novel determinant and potential therapeutic target for stimulating antitumor activity by macrophages.