The tumor suppressor menin prevents effector CD8 T-cell dysfunction by targeting mTORC1-dependent metabolic activation

Suzuki, Junpei; Yamada, Takeshi; Inoue, Kenzo; Nabe, Shogo; Kuwahara, Makoto; Takemori, Nobuaki; Takemori, Ayako; Matsuda, Seiji; Kanoh, Makoto; Imai, Yuuki; Yasukawa, Masaki; Yamashita, Masakatsu

doi:10.1038/s41467-018-05854-6

Cited by 55 publications

(56 citation statements)

References 68 publications

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“…18,34 Any condition causing even a modest variation in the cytosolic levels of aKG might affect different pathways, promoting either oncogenic or tumor suppressive responses: an increase of fatty acid biosynthesis or promotion of aberrant mammalian target of rapamycin 1 (mTORC1) activation ( Figure S3). [35][36][37] In addition, DLST mutation causing the loss of OGDH-complex nuclear-translocation capacity might lead to altered overall gene expression ( Figure S3). 38 The increased aKG to fumarate ratio in p.Gly374Glumutated tumors suggests that this variant leads to a disruption of OGDH complex activity.…”

Section: Discussionmentioning

confidence: 99%

Recurrent Germline DLST Mutations in Individuals with Multiple Pheochromocytomas and Paragangliomas

Remacha

Pirman

Mahoney

et al. 2019

The American Journal of Human Genetics

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Pheochromocytomas and paragangliomas (PPGLs) provide some of the clearest genetic evidence for the critical role of metabolism in the tumorigenesis process. Approximately 40% of PPGLs are caused by driver germline mutations in 16 known susceptibility genes, and approximately half of these genes encode members of the tricarboxylic acid (TCA) cycle. Taking as a starting point the involvement of the TCA cycle in PPGL development, we aimed to identify unreported mutations that occurred in genes involved in this key metabolic pathway and that could explain the phenotypes of additional individuals who lack mutations in known susceptibility genes. To accomplish this, we applied a targeted sequencing of 37 TCA-cycle-related genes to DNA from 104 PPGL-affected individuals with no mutations in the major known predisposing genes. We also performed omics-based analyses, TCA-related metabolite determination, and 13 C 5 -glutamate labeling assays. We identified five germline variants affecting DLST in eight unrelated individuals ($7%); all except one were diagnosed with multiple PPGLs. A recurrent variant, c.1121G>A (p.Gly374Glu), found in four of the eight individuals triggered accumulation of 2-hydroxyglutarate, both in tumors and in a heterologous cell-based assay designed to functionally evaluate DLST variants. p.Gly374Glu-DLST tumors exhibited loss of heterozygosity, and their methylation and expression profiles are similar to those of EPAS1-mutated PPGLs; this similarity suggests a link between DLST disruption and pseudohypoxia. Moreover, we found positive DLST immunostaining exclusively in tumors carrying TCA-cycle or EPAS1 mutations. In summary, this study reveals DLST as a PPGL-susceptibility gene and further strengthens the relevance of the TCA cycle in PPGL development.

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Section: Discussionmentioning

confidence: 99%

Recurrent Germline DLST Mutations in Individuals with Multiple Pheochromocytomas and Paragangliomas

Remacha

Pirman

Mahoney

et al. 2019

The American Journal of Human Genetics

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“…In evaluating the role an altered metabolic environment plays in the process of modifying CD8+ T-cell function, we found that key metabolites, including lactate, had unexpected functions in the activation of CD8+ T cells, with multiple TCA metabolites stimulating the loss of CD62L. CD62L shedding from TCR activated CD8+ T-cells has been suggested to be mTOR and PI3K dependent ( Sinclair et al, 2008 ) and aKG-mediated activation of mTORC1 has been reported in multiple cell lines ( DeBerardinis et al, 2007 ; Durán et al, 2013 ; Villar et al, 2015 ), as well as in activated CD8+ T-cells ( Suzuki et al, 2018 ), suggesting that the metabolite-induced loss of CD62L may be mediated through mTOR activation. In addition, we found that lactate induces an effector profile and an overall increase in cytotoxic activity.…”

Section: Discussionmentioning

confidence: 99%

Cytotoxic T-cells mediate exercise-induced reductions in tumor growth

Rundqvist

Veliça

Barbieri

et al. 2020

eLife

126

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Exercise has a wide range of systemic effects. In animal models, repeated exertion reduces malignant tumor progression, and clinically, exercise can improve outcome for cancer patients. The etiology of the effects of exercise on tumor progression are unclear, as are the cellular actors involved. We show here that in mice, exercise-induced reduction in tumor growth is dependent on CD8+ T cells, and that metabolites produced in skeletal muscle and excreted into plasma at high levels during exertion in both mice and humans enhance the effector profile of CD8+ T-cells. We found that activated murine CD8+ T cells alter their central carbon metabolism in response to exertion in vivo, and that immune cells from trained mice are more potent antitumor effector cells when transferred into tumor-bearing untrained animals. These data demonstrate that CD8+ T cells are metabolically altered by exercise in a manner that acts to improve their antitumoral efficacy.

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“…As discussed in the previous section, elevated expression of CD38 on T cells inversely regulates glutaminolysis, a predominant pathway of yielding α-KG, which act as a co-factor of histone and DNA demethylases [13,135]. Recently, it has been reported that α-KG mediated H3K27 demethylation can be linked to the increased effector cytokines (IFN-γ and IL-2) production by mouse CD8 + T cell [137]. The study arouses the possible association of CD38 dependent metabolic rewiring as a critical cellular event regulating the epigenetic modification of T cells and hence their functional state.…”

Section: Metabolites Mediated Epigenetic Regulationmentioning

confidence: 91%

CD38: T Cell Immuno-Metabolic Modulator

Kar

Mehrotra

Chatterjee

2020

Cells

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Activation and subsequent differentiation of T cells following antigenic stimulation are triggered by highly coordinated signaling events that lead to instilling cells with a discrete metabolic and transcriptional feature. Compelling studies indicate that intracellular nicotinamide adenine dinucleotide (NAD+) levels have profound influence on diverse signaling and metabolic pathways of T cells, and hence dictate their functional fate. CD38, a major mammalian NAD+ glycohydrolase (NADase), expresses on T cells following activation and appears to be an essential modulator of intracellular NAD+ levels. The enzymatic activity of CD38 in the process of generating the second messenger cADPR utilizes intracellular NAD+, and thus limits its availability to different NAD+ consuming enzymes (PARP, ART, and sirtuins) inside the cells. The present review discusses how the CD38-NAD+ axis affects T cell activation and differentiation through interfering with their signaling and metabolic processes. We also describe the pivotal role of the CD38-NAD+ axis in influencing the chromatin remodeling and rewiring T cell response. Overall, this review emphasizes the crucial contribution of the CD38−NAD+ axis in altering T cell response in various pathophysiological conditions.

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The tumor suppressor menin prevents effector CD8 T-cell dysfunction by targeting mTORC1-dependent metabolic activation

Cited by 55 publications

References 68 publications

Recurrent Germline DLST Mutations in Individuals with Multiple Pheochromocytomas and Paragangliomas

Recurrent Germline DLST Mutations in Individuals with Multiple Pheochromocytomas and Paragangliomas

Cytotoxic T-cells mediate exercise-induced reductions in tumor growth

CD38: T Cell Immuno-Metabolic Modulator

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