HIF-1α Is a Metabolic Switch between Glycolytic-Driven Migration and Oxidative Phosphorylation-Driven Immunosuppression of Tregs in Glioblastoma.

Abstract

The mechanisms by which regulatory T cells (Tregs) migrate to and function within the hypoxic tumor microenvironment are unclear. Our studies indicate that specific ablation of hypoxia-inducible factor 1α (HIF-1α) in Tregs results in enhanced CD8+ T cell suppression versus wild-type Tregs under hypoxia, due to increased pyruvate import into the mitochondria. Importantly, HIF-1α-deficient Tregs are minimally affected by the inhibition of lipid oxidation, a fuel that is critical for Treg metabolism in tumors. Under hypoxia, HIF-1α directs glucose away from mitochondria, leaving Tregs dependent on fatty acids for mitochondrial metabolism within the hypoxic tumor. Indeed, inhibition of lipid oxidation enhances the survival of mice with glioma. Interestingly, HIF-1α-deficient-Treg mice exhibit significantly enhanced animal survival in a murine model of glioma, due to their stymied migratory capacity, explaining their reduced abundance in tumor-bearing mice. Thus HIF-1α acts as a metabolic switch for Tregs between glycolytic-driven migration and oxidative phosphorylation-driven immunosuppression.

• Authors: Jason Miska, Catalina Lee-Chang, Aida Rashidi, Megan E Muroski, Alan L Chang, Aurora Lopez-Rosas, Peng Zhang, Wojciech K Panek, Alex Cordero, Yu Han, Atique U Ahmed, Navdeep S Chandel, Maciej S Lesniak
• Journal: Cell reports (Cell Rep) Vol. 27 Issue 1 Pg. 226-237.e4 (04 02 2019) ISSN: 2211-1247 [Electronic] United States
• PMID: 30943404 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit

Topics

• Aged
• Aged, 80 and over
• Animals
• Brain Neoplasms (genetics, immunology, metabolism, pathology)
• Cell Hypoxia (genetics, physiology)
• Cell Movement (genetics)
• Cells, Cultured
• Energy Metabolism (genetics)
• Female
• Genes, Switch (physiology)
• Glioblastoma (genetics, immunology, metabolism, pathology)
• Glycolysis (genetics)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, physiology)
• Immunosuppression Therapy
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Oxidative Phosphorylation
• T-Lymphocytes, Regulatory (immunology, metabolism)
• Tumor Escape (genetics, immunology)
• Tumor Microenvironment (genetics)