Hypoxia-inducible factor 1α plays a predominantly negative role in regulatory T cell functions

Hsu, Tzu-Sheng; Lai, Ming‐Zong

doi:10.1002/jlb.mr1217-481r

Cited by 27 publications

(16 citation statements)

References 61 publications

(136 reference statements)

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“…First, we determined that HIF-1α KO Tregs suppress better than HIF-1α WT Tregs under hypoxia, a notion in line with studies that suggest that HIF-1α antagonizes Foxp3 + suppressive function ( Hsiao et al, 2015 ; Hsu and Lai, 2018 ). Our results confirm that the immune suppressive capabilities of Tregs require mitochondrial metabolism, which has also been previously suggested ( Gerriets et al, 2015 ).…”

Section: Discussionsupporting

confidence: 59%

“… Dang et al (2011) demonstrated that the canonical hypoxia sensor, HIF-1α, negatively regulates Foxp3 expression while promoting TH17 differentiation. Other studies have also lent credence to the Treg-inhibitory actions of HIF-1α ( Hsiao et al, 2015 ; Hsu and Lai, 2018 ). However, other studies have shown that HIF-1α positively affects Treg function ( Ben-Shoshan et al, 2008 ; Clambey et al, 2012 ) and plays a role in their suppressive function in tumors ( Westendorf et al, 2017 ).…”

Section: Introductionmentioning

confidence: 86%

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

et al. 2019

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SUMMARY 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.

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Section: Discussionsupporting

confidence: 59%

Section: Introductionmentioning

confidence: 86%

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

et al. 2019

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“…Activation of the T cell receptor actually increases HIF‐1α downstream effects via PI3K/mTOR and protein kinase C mechanisms through stabilization of HIF‐1α even in the absence of hypoxia [140,177]. HIF‐1α promotes differentiation into FOXP3 + cells via increased gene transcription [178]. If sufficient TGF‐β is also present, then these cells become Tregs, but combined IL‐6 and HIF‐1α instead promotes Th17 cells [179,180].…”

Section: Helper and Regulatory T Cellsmentioning

confidence: 99%

“…These mechanisms are thought to be mediated by STAT3, which also decreases IFN‐γ production and decreases Th1 phenotype markers [177,180]. Interestingly, HIF‐1α can also bind to the FOXP3 protein to promote its degradation which can also promote Th17 and other pro‐inflammatory phenotypes [178]. HIF‐2α, however, does not promotes FOXP3 transcription in murine models of inflammation [179].…”

Section: Helper and Regulatory T Cellsmentioning

confidence: 99%

Hypoxia as a barrier to immunotherapy in pancreatic adenocarcinoma

Daniel

Sullivan

Labadie

et al. 2019

Clinical & Translational Med

162

109

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Pancreatic ductal adenocarcinoma (PDA) is a lethal disease with limited response to cytotoxic chemoradiotherapy, as well as newer immunotherapies. The PDA tumor microenvironment contains infiltrating immune cells including cytotoxic T cells; however, there is an overall immunosuppressive milieu. Hypoxia is a known element of the solid tumor microenvironment and may promote tumor survival. Through various mechanisms including, but not limited to, those mediated by HIF-1α, hypoxia also leads to increased tumor proliferation and metabolic changes. Furthermore, epithelial to mesenchymal transition is promoted through several pathways, including NOTCH and c-MET, regulated by hypoxia. Hypoxia-promoted changes also contribute to the immunosuppressive phenotype seen in many different cell types within the microenvironment and thereby may inhibit an effective immune system response to PDA. Pancreatic stellate cells (PSCs) and myofibroblasts appear to contribute to the recruitment of myeloid derived suppressor cells (MDSCs) and B cells in PDA via cytokines increased due to hypoxia. PSCs also increase collagen secretion in response to HIF-1α, which promotes a fibrotic stroma that alters T cell homing and migration. In hypoxic environments, B cells contribute to cytotoxic T cell exhaustion and produce chemokines to attract more immunosuppressive regulatory T cells. MDSCs inhibit T cell metabolism by hoarding key amino acids, modulate T cell homing by cleaving L-selectin, and prevent T cell activation by increasing PD-L1 expression. Immunosuppressive M2 phenotype macrophages promote T cell anergy via increased nitric oxide (NO) and decreased arginine in hypoxia. Increased numbers of regulatory T cells are seen in hypoxia which prevent effector T cell activation through cytokine production and increased CTLA-4. Effective immunotherapy for pancreatic adenocarcinoma and other solid tumors will need to help counteract the immunosuppressive nature of hypoxia-induced changes in the tumor microenvironment. Promising studies will look at combination therapies involving checkpoint inhibitors, chemokine inhibitors, and possible targeting of hypoxia. While no model is perfect, assuring that models incorporate the effects of hypoxia on cancer cells, stromal cells, and effector immune cells will be crucial in developing successful therapies.

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“…In addition, levels of essential amino acids in the tumor microenvironment can be low. Tumor infiltrating cell populations like myeloid-derived suppressor cells produce arginase, depleting arginine, while tumor-associated fibroblasts can break down the amino acid tryptophan, which also yields kynurenine a suppressive metabolite [4,37]. Thus, TIL have limited metabolic choices in the tumor microenvironment and this significantly impairs their effectiveness.…”

Section: Suppressive Mechanisms In the Tumor Microenvironmentmentioning

confidence: 99%

Metabolic Regulation of CAR T Cell Function by the Hypoxic Microenvironment in Solid Tumors

2019

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The field of immunometabolism has attracted growing attention as an area at the heart of immune regulation. Upon activation, T cells undergo significant metabolic changes allowing them to mediate effector responses. The advent of chimeric antigen receptor T cell-adoptive therapy has shown some striking clinical efficacy but fails to induce sufficient antitumor response in many patients. Solid tumors put up significant opposition creating a microenvironment deficient of oxygen and glucose, depriving T cells of energy and pushing them to exhaustion. Here, we focus on immune suppressive mechanisms related to hypoxia in the tumor microenvironment and the resulting metabolic changes in T cells. New therapeutic approaches such as generating chimeric antigen receptor T cells able to withstand the challenging solid tumor microenvironment are needed.

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Hypoxia-inducible factor 1α plays a predominantly negative role in regulatory T cell functions

Cited by 27 publications

References 61 publications

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

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

Hypoxia as a barrier to immunotherapy in pancreatic adenocarcinoma

Metabolic Regulation of CAR T Cell Function by the Hypoxic Microenvironment in Solid Tumors

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