D2HGDH-mediated D2HG catabolism enhances the anti-tumor activities of CAR-T cells in an immunosuppressive microenvironment

Yang, Quanjun; Hao, Juan; Chi, Mengyi; Wang, Yaxian; Li, Jie; Huang, Jinlu; Zhang, Jianping; Zhang, Mengqi; Lu, Jie; Zhou, Shu; Yuan, Ting; Shen, Zan; Zheng, Shuier; Guo, Cheng

doi:10.1016/j.ymthe.2022.01.007

Cited by 33 publications

(19 citation statements)

References 41 publications

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“…In addition, ECAR measures the rate of extracellular acidification, which mainly comes from the accumulation of lactic acid in the medium (glycolytic pathway) [64]. Among the studies reported, some used the Seahorse technology to explore the influence of CAR signaling tails (4-1BB vs. CD28) [49,65], while others focused on comparing CARs with either different designs or targets [52,[66][67][68][69], the additional secretory functions [53,70], the combination with PD-1/PD-L1 blockage [71], the polarization of the T cells [53,72], or the influence of co-expressing enzymes alongside the CARs in T cells [73,74]. The second injection of Oligomycin, an ATP synthase inhibitor, permits, through the measurement of ECAR, assessment of the maximum glycolytic capacity.…”

Section: Study Of Metabolism In Car T Cellsmentioning

confidence: 99%

Section: Car Modified To Enhance T Cell Resistance To Tmementioning

confidence: 99%

“…Finally, two recent studies [73,74] evaluated the impact of the co-expression of enzymes affecting metabolism, alongside CARs, in order to generate constructs equipped to fight a strong TME. The enzymes used, Lactobacillus brevis NADH Oxidase (LbNOX) [73] and D-2-hydroxyglutarate dehydrogenase (D2HGDH) [74], were expected to provide resistance to the TME by affecting mitochondrial respiration. Co-expression of LbNOX with a mesothelin-specific CD28ζ CAR (CAR_Nox) induced higher levels of baseline OCR compared to a CD28ζ CAR co-expressed with GFP (CAR_GFP), reaching levels similar to those of untransduced T cells.…”

Section: Car Modified To Enhance T Cell Resistance To Tmementioning

confidence: 99%

“…Therefore, co-expressing LbNox with the CAR in T cells resulted in enhanced oxygen and lactate consumption, as well as increased pyruvate production and resiliency to lactate dehydrogenase inhibition but did not confer an increased antitumor efficiency in vivo. The second study was more promising; Yang et al [74] tested CD19 CAR T cells with a D2HGDH knocked-out (KO) or overexpressed (OE) backgrounds. D2HGDH is a mitochondrial protein shown to catabolize a component present at high levels in the TME, D-2-hydroxyglutarate (D2HG).…”

Section: Car Modified To Enhance T Cell Resistance To Tmementioning

confidence: 99%

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How CAR T Cells Breathe

Forcados

Joaquina

Casey

et al. 2022

Cells

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The manufacture of efficacious CAR T cells represents a major challenge in cellular therapy. An important aspect of their quality concerns energy production and consumption, known as metabolism. T cells tend to adopt diverse metabolic profiles depending on their differentiation state and their stimulation level. It is therefore expected that the introduction of a synthetic molecule such as CAR, activating endogenous signaling pathways, will affect metabolism. In addition, upon patient treatment, the tumor microenvironment might influence the CAR T cell metabolism by compromising the energy resources. The access to novel technology with higher throughput and reduced cost has led to an increased interest in studying metabolism. Indeed, methods to quantify glycolysis and mitochondrial respiration have been available for decades but were rarely applied in the context of CAR T cell therapy before the release of the Seahorse XF apparatus. The present review will focus on the use of this instrument in the context of studies describing the impact of CAR on T cell metabolism and the strategies to render of CAR T cells more metabolically fit.

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Section: Study Of Metabolism In Car T Cellsmentioning

confidence: 99%

Section: Car Modified To Enhance T Cell Resistance To Tmementioning

confidence: 99%

Section: Car Modified To Enhance T Cell Resistance To Tmementioning

confidence: 99%

Section: Car Modified To Enhance T Cell Resistance To Tmementioning

confidence: 99%

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How CAR T Cells Breathe

Forcados

Joaquina

Casey

et al. 2022

Cells

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“…Due to the differential 2HG accumulation in the tumour microenvironment, it is becoming increasingly important to determine whether the two enantiomers of 2HG act in a similar fashion in immune cells, or whether the two enantiomers should be considered as clearly separate biological agents from a mechanistic standpoint. As both enantiomers can affect cytotoxic T cell differentiation, proliferation, and function (Du and Hu, 2021; Foskolou et al, 2020; Tyrakis et al, 2016; Yang et al, 2022), we wished to determine the extent to which they have clearly differentiable roles in CD8+ T cell function. We show here that the two enantiomers are qualitatively separable in their actions and should be considered as two separate actors in regulating T cell function.…”

Section: Introductionmentioning

confidence: 99%

The two enantiomers of 2-hydroxyglutarate differentially regulate cytotoxic T cell function

Foskolou

Cunha

Minogue

et al. 2022

Preprint

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2-hydroxyglutarate (2HG) is a by-product of the TCA cycle, and is readily detected in the tissues of healthy individuals. 2HG is found in two enantiomeric forms: S-2HG and R-2HG. Here, we investigate the differential roles of these two enantiomers in CD8+ T cell biology, where we found they had highly divergent effects on proliferation, differentiation, and T cell function. We show here an analysis of structural determinants that likely underlie these differential effects on specific aketoglutarate (aKG)-dependent enzymes. Treatment of CD8+ T cells with exogenous S-2HG, but not R-2HG, increased CD8+ T cell fitness in vivo, and enhanced antitumour activity. These data show that S-2HG and R-2HG should be considered as two distinct and important actors in the regulation of T cell function.

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D2HGDH Deficiency Regulates Seizures through GSH/Prdx6/ROS‐Mediated Excitatory Synaptic Activity

Zhang,

Zhang

et al. 2024

Advanced Science

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Current antiepileptic drugs are ineffective in one‐third of patients with epilepsy; however, identification of genes involved in epilepsy can enable a precision medicine approach. Here, it is demonstrated that downregulating D‐2‐hydroxyglutarate dehydrogenase (D2HGDH) enhances susceptibility to epilepsy. Furthermore, its potential involvement in the seizure network through synaptic function modulation is investigated. D2HGDH knockdown reduces the glutathione reduced (GSH)/glutathione oxidized (GSSG) ratio and elevates reactive oxygen species (ROS) levels within neurons. Oxidative stress may play a crucial role in the pathogenesis of epilepsy. The specific contribution of each pathway varies among patients, highlighting the complexity of this disease. In this study, downregulation of D2HGDH affects modulation of ROS levels, synaptic transmission, and seizure susceptibility. Furthermore, the acid calcium‐independent phospholipase A2 (aiPLA2) inhibitor, MJ33, restores the GSH/GSSG balance and reverses the increase in ROS levels caused by D2HGDH knockdown, resulting in remission of epilepsy‐related behaviors. The results demonstrate that downregulation of D2HGDH affects synaptic function by regulating ROS production. These findings support the use of targeted gene therapy as a potential alternative to antioxidant‐based treatments for refractory epilepsy.

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D2HGDH-mediated D2HG catabolism enhances the anti-tumor activities of CAR-T cells in an immunosuppressive microenvironment

Cited by 33 publications

References 41 publications

How CAR T Cells Breathe

How CAR T Cells Breathe

The two enantiomers of 2-hydroxyglutarate differentially regulate cytotoxic T cell function

D2HGDH Deficiency Regulates Seizures through GSH/Prdx6/ROS‐Mediated Excitatory Synaptic Activity

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