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

Abstract

SUMMARY 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)-ULK1and autophagypathways, 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, auto-phagy, and CEBPB pathways to affect MDSCs and maintain tumor immunosuppression.

High-salt diet inhibits tumour growth in mice via regulating myeloid-derived suppressor cell differentiation

“…HSD enhanced T-cell-mediated antitumour responses. MDSC accumulation was associated with a reduction in T-cell-mediated antitumour activity during tumour progression 33 . Therefore, we investigated whether promoting MDSC differentiation and inhibiting its immunosuppressive functions by HSD would affect the proliferation and functions of CD4 + T and CD8 + T cells in tumour animal models.…”

DDIT3 modulates cancer stemness in gastric cancer by directly regulating CEBPβ

“…Evidence has shown that CEBPβ plays an important role in adipogenesis in mice, [26] and hepatocyte proliferation in liver regeneration [27] . Furthermore, CEBPβ mediates cell cycle, autophagy and senescence in various cancers [28–30] . And a recent study revealed that CEBPβ mediates the expression of CD133, which is a cellular surface protein of CSCs, indicating that CEBPβ might involve in the CSCs stemness.…”

Metabolic Regulation of Myeloid-Derived Suppressor Cell Function in Cancer

“…Excess lactate is transported across membranes by monocarboxylate transporters (MCT)1 and MCT4, which play vital roles in tumor aggressiveness [45,46]. Liver-enriched activator protein (LAP), an isoform of C/EBPβ, has been found in patients with triple-negative breast cancer and controls the expression of G-CSF and GM-CSF, thus promoting the development of MDSCs [47]. Restriction of aerobic glycolysis restrains the translation of LAP by stimulating AMPK-ULK and the autophagy pathway to impact the immunosuppression of MDSCs [47].…”

“…Liver-enriched activator protein (LAP), an isoform of C/EBPβ, has been found in patients with triple-negative breast cancer and controls the expression of G-CSF and GM-CSF, thus promoting the development of MDSCs [47]. Restriction of aerobic glycolysis restrains the translation of LAP by stimulating AMPK-ULK and the autophagy pathway to impact the immunosuppression of MDSCs [47]. The glycolytic genes and metabolic rate of glycolysis in MDSCs are also upregulated in the TME to generate large amounts of phosphoenolpyruvate (PEP) by glycolysis, which, as an antioxidant agent, blunts the production of ROS to avoid ROS-mediated apoptosis [48].…”