Sirt2 Inhibition Reprograms T Cell Metabolism to Confer Superior Anti-Tumor Immunity
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA635802 | ENA |
REPOSITORIES: ENA
Dataset's files
| 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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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.
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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.
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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.
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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.
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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.
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Project description:Mycobacterium bovis Bacillus Calmette-Guérin (BCG) is the vaccine against tuberculosis and an immunotherapy for bladder cancer. When administered intravenously, BCG reprograms bone marrow hematopoietic stem and progenitor cells (HSPCs), leading to heterologous protection against infections. Whether HSPC reprogramming contributes to the anti-tumor effects of BCG administered into the bladder is unknown. We demonstrate that BCG administered in the bladder colonizes the bone marrow and, in both mice and humans, reprograms HSPCs to alter and amplify myelopoiesis. BCG-reprogrammed HSPCs are sufficient to confer augmented anti-tumor immunity through production of neutrophils, monocytes, and dendritic cells that broadly remodel the tumor microenvironment, drive T cell-dependent anti-tumor responses, and synergize with checkpoint blockade. We conclude that bladder BCG acts systemically through hematopoiesis, highlighting the broad potential of HSPC reprogramming to enhance the innate drivers of T cell-dependent tumor immunity.
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Project description:Mycobacterium bovis Bacillus Calmette-Guérin (BCG) is the vaccine against tuberculosis and an immunotherapy for bladder cancer. When administered intravenously, BCG reprograms bone marrow hematopoietic stem and progenitor cells (HSPCs), leading to heterologous protection against infections. Whether HSPC reprogramming contributes to the anti-tumor effects of BCG administered into the bladder is unknown. We demonstrate that BCG administered in the bladder colonizes the bone marrow and, in both mice and humans, reprograms HSPCs to alter and amplify myelopoiesis. BCG-reprogrammed HSPCs are sufficient to confer augmented anti-tumor immunity through production of neutrophils, monocytes, and dendritic cells that broadly remodel the tumor microenvironment, drive T cell-dependent anti-tumor responses, and synergize with checkpoint blockade. We conclude that bladder BCG acts systemically through hematopoiesis, highlighting the broad potential of HSPC reprogramming to enhance the innate drivers of T cell-dependent tumor immunity.
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