Lactate Limits T Cell Proliferation via the NAD(H) Redox State

Quinn, William J.; Jiao, Jing; TeSlaa, Tara; Stadanlick, Jason; Wang, Zhong Lin; Wang, Liqing; Akimova, Tatiana; Angelin, Alessia; Schäfer, Patrick; Cully, Michelle D.; Perry, Caroline; Kopiński, Piotr; Guo, Lili; Blair, Ian A.; Ghanem, Louis; Leibowitz, Michael S.; Hancock, Wayne W.; Moon, Edmund K.; Levine, Matthew H.; Eruslanov, Evgeniy; Wallace, Douglas C.; Baur, Joseph A.; Beier, Ulf H.

doi:10.1016/j.celrep.2020.108500

Cited by 173 publications

(128 citation statements)

References 49 publications

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“…H + ions inhibit phosphofructokinase activity ( Dobson et al, 1986 ; Leite et al, 2011 ), and lactate is converted to pyruvate by lactate dehydrogenase, which impairs NADH recycling ( Gray et al, 2014 ; Angelin et al, 2017 ). Because NAD + is necessary for glyceraldehyde 3-phosphate dehydrogenase (GAPDH) function, NAD + is needed for sustained glycolysis ( Quinn et al, 2020 ). Lactate and the associated H + ions have similar inhibitory effects on glycolysis in immune cells ( Figure 1 ).…”

Section: Receptor Transport and Metabolismmentioning

confidence: 99%

Lactate Is a Metabolic Mediator That Shapes Immune Cell Fate and Function

et al. 2021

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Lactate and the associated H+ ions are still introduced in many biochemistry and general biology textbooks and courses as a metabolic by-product within fast or oxygen-independent glycolysis. However, the role of lactate as a fuel source has been well-appreciated in the field of physiology, and the role of lactate as a metabolic feedback regulator and distinct signaling molecule is beginning to gain traction in the field of immunology. We now know that while lactate and the associated H+ ions are generally immunosuppressive negative regulators, there are cell, receptor, mediator, and microenvironment-specific effects that augment T helper (Th)17, macrophage (M)2, tumor-associated macrophage, and neutrophil functions. Moreover, we are beginning to uncover how lactate and H+ utilize different transporters and signaling cascades in various immune cell types. These immunomodulatory effects may have a substantial impact in cancer, sepsis, autoimmunity, wound healing, and other immunomodulatory conditions with elevated lactate levels. In this article, we summarize the known effects of lactate and H+ on immune cells to hypothesize potential explanations for the divergent inflammatory vs. anti-inflammatory effects.

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Section: Receptor Transport and Metabolismmentioning

confidence: 99%

Lactate Is a Metabolic Mediator That Shapes Immune Cell Fate and Function

et al. 2021

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“…Consequently, an inability to recirculate cytoplasmic NAD + and sustain glycolysis impairs ATP production, nucleotide biosynthesis and overall proliferation. Quinn and colleagues showed that exposure to high-lactate, low-glucose environments induced such reductive stress, culminating in decreased glycolysis and reduced serine production, in effector as well as regulatory T cells [ 40 ]. This may explain why (in the aforementioned study by Uhl and coworkers) the addition of oligomycin to the glycolytic stress test assay led to a decrease instead of an expected increase in ECAR in some assays.…”

Section: Metabolic Consequences Of Lactic Acid On T Cell Functionmentioning

confidence: 99%

Beyond the Lactate Paradox: How Lactate and Acidity Impact T Cell Therapies against Cancer

Ayari

O’Connor

2021

Antibodies

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T cell therapies, including CAR T cells, have proven more effective in hematologic malignancies than solid tumors, where the local metabolic environment is distinctly immunosuppressive. In particular, the acidic and hypoxic features of the tumor microenvironment (TME) present a unique challenge for T cells. Local metabolism is an important consideration for activated T cells as they undergo bursts of migration, proliferation and differentiation in hostile soil. Tumor cells and activated T cells both produce lactic acid at high rates. The role of lactic acid in T cell biology is complex, as lactate is an often-neglected carbon source that can fuel TCA anaplerosis. Circulating lactate is also an important means to regulate redox balance. In hypoxic tumors, lactate is immune-suppressive. Here, we discuss how intrinsic- (T cells) as well as extrinsic (tumor cells and micro-environmental)-derived metabolic factors, including lactate, suppress the ability of antigen-specific T cells to eradicate tumors. Finally, we introduce recent discoveries that target the TME in order to potentiate T cell-based therapies against cancer.

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“…Such parallels can be drawn between the lymph node microenvironment and TME, whereby lactate inhibits the effector T cell function [ 20 ]. Excess lactate impairs NAD+ regeneration, subsequently blocking the enzymatic reactions involving glyceraldehyde 3-phosphate dehydrogenase and 3-phosphoglycerate dehydrogenase [ 21 ]. This blockade reduces T cell proliferation, but can be rescued by restoration of the redox balance via supplementation with serine [ 21 ].…”

Section: T Cell Metabolism and The Tumour Microenvironmentmentioning

confidence: 99%

“…Excess lactate impairs NAD+ regeneration, subsequently blocking the enzymatic reactions involving glyceraldehyde 3-phosphate dehydrogenase and 3-phosphoglycerate dehydrogenase [ 21 ]. This blockade reduces T cell proliferation, but can be rescued by restoration of the redox balance via supplementation with serine [ 21 ]. Furthermore, within the TME, lactate can promote the differentiation of naïve T cells into regulatory T cells (Tregs) whereby the carbon backbone directly enters the citric acid (TCA) cycle and contributes to energy production via OXPHOS.…”

Section: T Cell Metabolism and The Tumour Microenvironmentmentioning

confidence: 99%

Tinkering under the Hood: Metabolic Optimisation of CAR-T Cell Therapy

et al. 2021

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Chimeric antigen receptor (CAR)-T cells are one of the most exciting areas of immunotherapy to date. Clinically available CAR-T cells are used to treat advanced haematological B-cell malignancies with complete remission achieved at around 30–40%. Unfortunately, CAR-T cell success rates are even less impressive when considering a solid tumour. Reasons for this include the paucity of tumour specific targets and greater degree of co-expression on normal tissues. However, there is accumulating evidence that considerable competition for nutrients such as carbohydrates and amino acids within the tumour microenvironment (TME) coupled with immunosuppression result in mitochondrial dysfunction, exhaustion, and subsequent CAR-T cell depletion. In this review, we will examine research avenues being pursued to dissect the various mechanisms contributing to the immunosuppressive TME and outline in vitro strategies currently under investigation that focus on boosting the metabolic program of CAR-T cells as a mechanism to overcome the immunosuppressive TME. Various in vitro and in vivo techniques boost oxidative phosphorylation and mitochondrial fitness in CAR-T cells, resulting in an enhanced central memory T cell compartment and increased anti-tumoural immunity. These include intracellular metabolic enhancers and extracellular in vitro culture optimisation pre-infusion. It is likely that the next generation of CAR-T products will incorporate these elements of metabolic manipulation in CAR-T cell design and manufacture. Given the importance of immunometabolism and T cell function, it is critical that we identify ways to metabolically armour CAR-T cells to overcome the hostile TME and increase clinical efficacy.

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Lactate Limits T Cell Proliferation via the NAD(H) Redox State

Cited by 173 publications

References 49 publications

Lactate Is a Metabolic Mediator That Shapes Immune Cell Fate and Function

Lactate Is a Metabolic Mediator That Shapes Immune Cell Fate and Function

Beyond the Lactate Paradox: How Lactate and Acidity Impact T Cell Therapies against Cancer

Tinkering under the Hood: Metabolic Optimisation of CAR-T Cell Therapy

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