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

Jason Michael 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 Uddin Ahmed, Navdeep Chandel, Maciej S Lesniak*

*Corresponding author for this work

Research output: Contribution to journalArticle

2 Citations (Scopus)

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. Miska et al. demonstrate that regulatory T cell (Treg)-specific depletion of HIF-1α promotes enhanced immune suppression at the cost of migration under hypoxic conditions. Within the hypoxic brain-tumor environment, Tregs are uniquely able to metabolize extracellular free fatty acids to promote their immunosuppressive functionality, which can be targeted in vivo.

Original languageEnglish (US)
Pages (from-to)226-237.e4
JournalCell reports
Volume27
Issue number1
DOIs
StatePublished - Apr 2 2019

Fingerprint

Hypoxia-Inducible Factor 1
Oxidative Phosphorylation
Glioblastoma
Immunosuppression
Switches
Tumors
T-cells
Mitochondria
Regulatory T-Lymphocytes
Metabolism
Glioma
Bearings (structural)
Enzyme inhibition
Lipids
Neoplasms
Oxidation
Tumor Microenvironment
Immunosuppressive Agents
Ablation
Pyruvic Acid

Keywords

  • fatty acid oxidation
  • glioblastoma
  • glycolysis
  • immunosuppression
  • migration
  • oxidative phosphorylation
  • regulatory T cell

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Miska, Jason Michael ; Lee Chang, Catalina ; Rashidi, Aida ; Muroski, Megan E. ; Chang, Alan L. ; Lopez-Rosas, Aurora ; Zhang, Peng ; Panek, Wojciech K. ; Cordero, Alex ; Han, Yu ; Ahmed, Atique Uddin ; Chandel, Navdeep ; Lesniak, Maciej S. / HIF-1α Is a Metabolic Switch between Glycolytic-Driven Migration and Oxidative Phosphorylation-Driven Immunosuppression of Tregs in Glioblastoma. In: Cell reports. 2019 ; Vol. 27, No. 1. pp. 226-237.e4.
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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. Miska et al. demonstrate that regulatory T cell (Treg)-specific depletion of HIF-1α promotes enhanced immune suppression at the cost of migration under hypoxic conditions. Within the hypoxic brain-tumor environment, Tregs are uniquely able to metabolize extracellular free fatty acids to promote their immunosuppressive functionality, which can be targeted in vivo.",
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HIF-1α Is a Metabolic Switch between Glycolytic-Driven Migration and Oxidative Phosphorylation-Driven Immunosuppression of Tregs in Glioblastoma. / Miska, Jason Michael; Lee Chang, Catalina; Rashidi, Aida; Muroski, Megan E.; Chang, Alan L.; Lopez-Rosas, Aurora; Zhang, Peng; Panek, Wojciech K.; Cordero, Alex; Han, Yu; Ahmed, Atique Uddin; Chandel, Navdeep; Lesniak, Maciej S.

In: Cell reports, Vol. 27, No. 1, 02.04.2019, p. 226-237.e4.

Research output: Contribution to journalArticle

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T1 - HIF-1α Is a Metabolic Switch between Glycolytic-Driven Migration and Oxidative Phosphorylation-Driven Immunosuppression of Tregs in Glioblastoma

AU - Miska, Jason Michael

AU - Lee Chang, Catalina

AU - Rashidi, Aida

AU - Muroski, Megan E.

AU - Chang, Alan L.

AU - Lopez-Rosas, Aurora

AU - Zhang, Peng

AU - Panek, Wojciech K.

AU - Cordero, Alex

AU - Han, Yu

AU - Ahmed, Atique Uddin

AU - Chandel, Navdeep

AU - Lesniak, Maciej S

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Y1 - 2019/4/2

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AB - 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. Miska et al. demonstrate that regulatory T cell (Treg)-specific depletion of HIF-1α promotes enhanced immune suppression at the cost of migration under hypoxic conditions. Within the hypoxic brain-tumor environment, Tregs are uniquely able to metabolize extracellular free fatty acids to promote their immunosuppressive functionality, which can be targeted in vivo.

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