Aerobic Glycolysis Controls Myeloid-Derived Suppressor Cells and Tumor Immunity via a Specific CEBPB Isoform in Triple-Negative Breast Cancer.

Cell metabolism 2018 Jul 03

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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. Published by Elsevier Inc.

Citation

Wei Li, Takashi Tanikawa, Ilona Kryczek, Houjun Xia, Gaopeng Li, Ke Wu, Shuang Wei, Lili Zhao, Linda Vatan, Bo Wen, Pan Shu, Duxin Sun, Celina Kleer, Max Wicha, Michael Sabel, Kaixiong Tao, Guobin Wang, Weiping Zou. Aerobic Glycolysis Controls Myeloid-Derived Suppressor Cells and Tumor Immunity via a Specific CEBPB Isoform in Triple-Negative Breast Cancer. Cell metabolism. 2018 Jul 03;28(1):87-103.e6