HIF1α-regulated glycolysis promotes activation-induced cell death and IFN-γ induction in hypoxic T cells

Hongxing Shen, Oluwagbemiga A. Ojo, Haitao Ding, Logan J. Mullen, Chuan Xing, M. Iqbal Hossain, Abdelrahman Yassin, Vivian Y. Shi, Zach Lewis, Ewa Podgorska, Shaida A. Andrabi, Maciek R. Antoniewicz, James A. Bonner and Lewis Zhichang Shi ()
Additional contact information
Hongxing Shen: University of Alabama at Birmingham (UAB-SOM)
Oluwagbemiga A. Ojo: University of Alabama at Birmingham (UAB-SOM)
Haitao Ding: University of Alabama at Birmingham (UAB-SOM)
Logan J. Mullen: University of Alaska Fairbanks
Chuan Xing: University of Alabama at Birmingham (UAB-SOM)
M. Iqbal Hossain: UAB-SOM
Abdelrahman Yassin: University of Alabama at Birmingham (UAB-SOM)
Vivian Y. Shi: University of Alabama at Birmingham (UAB-SOM)
Zach Lewis: University of Alabama at Birmingham (UAB-SOM)
Ewa Podgorska: University of Alabama at Birmingham (UAB-SOM)
Shaida A. Andrabi: UAB-SOM
Maciek R. Antoniewicz: University of Michigan
James A. Bonner: University of Alabama at Birmingham (UAB-SOM)
Lewis Zhichang Shi: University of Alabama at Birmingham (UAB-SOM)

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Hypoxia is a common feature in various pathophysiological contexts, including tumor microenvironment, and IFN-γ is instrumental for anti-tumor immunity. HIF1α has long been known as a primary regulator of cellular adaptive responses to hypoxia, but its role in IFN-γ induction in hypoxic T cells is unknown. Here, we show that the HIF1α-glycolysis axis controls IFN-γ induction in both human and mouse T cells, activated under hypoxia. Specific deletion of HIF1α in T cells (Hif1α–/–) and glycolytic inhibition suppresses IFN-γ induction. Conversely, HIF1α stabilization by hypoxia and VHL deletion in T cells (Vhl–/–) increases IFN-γ production. Hypoxic Hif1α–/– T cells are less able to kill tumor cells in vitro, and tumor-bearing Hif1α–/– mice are not responsive to immune checkpoint blockade (ICB) therapy in vivo. Mechanistically, loss of HIF1α greatly diminishes glycolytic activity in hypoxic T cells, resulting in depleted intracellular acetyl-CoA and attenuated activation-induced cell death (AICD). Restoration of intracellular acetyl-CoA by acetate supplementation re-engages AICD, rescuing IFN-γ production in hypoxic Hif1α–/– T cells and re-sensitizing Hif1α–/– tumor-bearing mice to ICB. In summary, we identify HIF1α-regulated glycolysis as a key metabolic control of IFN-γ production in hypoxic T cells and ICB response.

Date: 2024
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DOI: 10.1038/s41467-024-53593-8

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