Department of Surgery, University of Michigan School of Medicine, BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109-0669, USA; Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1277, Wuhan, Hubei 430022, China.
Department of Surgery, University of Michigan School of Medicine, BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109-0669, USA.
Cell Metab. 2018 Jul 3;28(1):87-103.e6. doi: 10.1016/j.cmet.2018.04.022. Epub 2018 May 24.
Myeloid-derived suppressor cells (MDSCs) inhibit anti-tumor immunity. Aerobic glycolysis is a hallmark of cancer. However, the link between MDSCs and glycolysis is unknown in patients with triple-negative breast cancer (TNBC). Here, we detect abundant glycolytic activities in human TNBC. In two TNBC mouse models, 4T1 and Py8119, glycolysis restriction inhibits tumor granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage colony-stimulating factor (GM-CSF) expression and reduces MDSCs. These are accompanied with enhanced T cell immunity, reduced tumor growth and metastasis, and prolonged mouse survival. Mechanistically, glycolysis restriction represses the expression of a specific CCAAT/enhancer-binding protein beta (CEBPB) isoform, liver-enriched activator protein (LAP), via the AMP-activated protein kinase (AMPK)-ULK1 and autophagy pathways, whereas LAP controls G-CSF and GM-CSF expression to support MDSC development. Glycolytic signatures that include lactate dehydrogenase A correlate with high MDSCs and low T cells, and are associated with poor human TNBC outcome. Collectively, tumor glycolysis orchestrates a molecular network of the AMPK-ULK1, autophagy, and CEBPB pathways to affect MDSCs and maintain tumor immunosuppression.
髓系来源的抑制细胞（MDSCs）抑制抗肿瘤免疫。有氧糖酵解是癌症的一个标志。然而，在三阴性乳腺癌（TNBC）患者中，MDSCs 与糖酵解之间的联系尚不清楚。在这里，我们在人类 TNBC 中检测到丰富的糖酵解活性。在两种 TNBC 小鼠模型（4T1 和 Py8119）中，糖酵解限制抑制肿瘤粒细胞集落刺激因子（G-CSF）和粒细胞巨噬细胞集落刺激因子（GM-CSF）的表达，并减少 MDSCs。这伴随着增强的 T 细胞免疫、减少肿瘤生长和转移以及延长小鼠存活。从机制上讲，糖酵解限制通过 AMP 激活蛋白激酶（AMPK）-ULK1 和自噬途径抑制特定的 CCAAT/增强子结合蛋白β（CEBPB）异构体肝丰富激活蛋白（LAP）的表达，而 LAP 控制 G-CSF 和 GM-CSF 的表达以支持 MDSC 的发育。包括乳酸脱氢酶 A 在内的糖酵解特征与高 MDSCs 和低 T 细胞相关，并与人类 TNBC 的不良预后相关。总的来说，肿瘤糖酵解协调了 AMPK-ULK1、自噬和 CEBPB 途径的分子网络，以影响 MDSC 并维持肿瘤免疫抑制。
