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Sirt2 Inhibition Reprograms T Cell Metabolism to Confer Superior Anti-Tumor Immunity

ABSTRACT: Sirt2 Inhibition Reprograms T Cell Metabolism to Confer Superior Anti-Tumor Immunity

PROVIDER: PRJNA635802 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11873700_1.fastq.gz	Fastqsanger.gz
	SRR11873700_2.fastq.gz	Fastqsanger.gz
	SRR11873701_1.fastq.gz	Fastqsanger.gz
	SRR11873701_2.fastq.gz	Fastqsanger.gz
	SRR11873702_1.fastq.gz	Fastqsanger.gz

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Sirt2 Inhibition Reprograms T Cell Metabolism to Confer Superior Anti-Tumor Immunity

Project description:Metabolism is a key driver of T cell functions, and the switch from oxidative-phosphorylation to aerobic glycolysis is a hallmark of T cell activation. However, the mechanisms underlying the metabolic switch remain unclear. Here, we report that the Sirtuin-2 (Sirt2) deacetylase protein functions as a metabolic checkpoint that harnesses T cell effector functions and impairs anti-tumor immunity. Specifically, upregulation of Sirt2 expression in human tumor-infiltrating T lymphocytes (TILs) negatively correlates with response to Nivolumab and TIL therapy in non-small cell lung cancer. Mechanistically, Sirt2 suppresses aerobic glycolysis by deacetylating key glycolytic enzymes. Accordingly, Sirt2-deficient T cells manifest increased glycolysis, display enhanced proliferation and effector functions, and have superior anti-tumor activity. Importantly, pharmacologic inhibition of Sirt2 endows human TILs with these superior metabolic fitness and enhanced effector functions. These findings indicate Sirt2 as an actionable target for reprogramming T cell metabolism to augment a broad spectrum of cancer immunotherapies.

2020-09-16 | GSE151421 | GEO

Sirt2 Inhibition Reprograms T Cell Metabolism to Confer Superior Anti-Tumor Immunity

Project description:Dysregulated metabolism is a key driver of maladaptive tumor-reactive T lymphocytes within the tumor microenvironment (TME). Actionable mechanisms that rescue the effector activity of anti-tumor T cells in a metabolically restricted TME remain elusive. Here, we report that the Sirtuin-2 (Sirt2) protein deacetylase functions as a master metabolic checkpoint that inhibits T cell metabolic fitness and impairs T cell effector functions and anti-tumor immunity. Mechanistically, Sirt2 suppresses glycolysis and oxidative-phosphorylation (OxPhos) by deacetylating key enzymes involved in glycolysis, tricarboxylic acid (TCA)-cycle, fatty acid oxidation (FAO) and glutaminolysis. Accordingly, Sirt2-deficient T cells exhibit a hyper-metabolic activity with increased glycolysis and OxPhos, resulting in enhanced proliferation and effector functions at tumor beds and subsequently exhibiting superior anti-tumor activity. Importantly, pharmacologic inhibition of Sirt2 endows human lung tumor-infiltrating lymphocytes (TILs) with these superior metabolic fitness and enhanced effector functions. Furthermore, upregulation of Sirt2 expression in human TILs negatively correlates with response to Nivolumab and TIL therapy in non-small cell lung cancer (NSCLC). Our findings unveil Sirt2 as an unexpected actionable target for reprogramming T cell metabolism to augment a broad spectrum of cancer immunotherapies.

2020-06-16 | PXD019763 | Pride

Sirt2 inhibition reprograms T cell metabolism for optimal anti-tumor immunity: Sirt2 Interacting Proteins

Project description:Growing evidence indicates that metabolism is a key driver of T cell functions. A switch from oxidative phosphorylation to aerobic glycolysis is a hallmark of T cell activation and is required to meet metabolic demands of proliferation and effector functions. However, the mechanisms underlying the metabolic switch in T cells remain unclear. Here, we identify Sirt2 as a crucial immune checkpoint coordinating metabolic and functional fitness of T cells. Sirt2 is induced upon T cell activation and increases in late maturation stages. Sirt2 negatively regulates glycolysis by targeting key glycolytic enzymes. Remarkably, Sirt2 knockout T cells exhibit profound upregulation of aerobic glycolysis with enhanced proliferation and effector function and thus effectively reject tumor challenge in vivo. Furthermore, pharmacologic inhibition of Sirt2 in human tumor infiltrating lymphocytes demonstrated a similar phenotype. Taken together, our results demonstrate Sirt2 as an actionable target to reprogram T cell metabolism to augment immunotherapy.

2020-06-15 | PXD012811 | Pride

Sirt2 inhibition reprograms T cell metabolism for optimal anti-tumor immunity: Sirt2 Interacting Proteins 2

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Sirt2 inhibition reprograms T cell metabolism for optimal anti-tumor immunity: Lysine Acetylation

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Octopamine metabolically reprograms astrocytes to confer neuroprotection against α-synuclein

Project description:Octopamine metabolically reprograms astrocytes to confer neuroprotection against α-synuclein

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Project description:We provide evidence for the essential role of Sirt2 in IFN mediated signaling. Our studies demonstrate that SIRT2 controls expression of key interferon stimulated genes (ISGs) that mediate important biological functions, including anti-viral and antineoplastic responses.

2015-12-31 | GSE66033 | GEO

Deacetylation of Sirt2 regulates PKM2 ubiquitination and its effect on liver glucose metabolism

Project description:In order to explore the effects of SIRT2 on the liver metabolic function of mice under metabolic stress, we constructed SIRT2 knockout mice.

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2013-06-01 | E-MEXP-3912 | biostudies-arrayexpress