Role of Sirt2 in T Cell Metabolism
Sirt2 在 T 细胞代谢中的作用
基本信息
- 批准号:10352407
- 负责人:
- 金额:$ 37.68万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-03-01 至 2026-02-28
- 项目状态:未结题
- 来源:
- 关键词:AcetylationAgingAnimalsAttentionBedsCTAG1 geneCancer PatientCell physiologyCellsCellular Metabolic ProcessCitric Acid CycleComplementDataDeacetylaseDevelopmentEnzymesGenesGenetic EngineeringGenetic studyGlucoseGlutamineGlycolysisHistone DeacetylaseHumanHuman EngineeringImmuneImmune TargetingImmune responseImmunologicsImmunotherapeutic agentImmunotherapyImpairmentIn VitroLaboratoriesMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of lungMediatingMemoryMetabolicMetabolismModelingMolecularMolecular BiologyMolecular GeneticsMusNivolumabNon-Small-Cell Lung CarcinomaOxidative PhosphorylationPatientsPharmacologyPhenotypePhysiologicalPost-Translational Protein ProcessingProtein AcetylationProteinsProteomicsReproducibilityResistanceResveratrolRoleSamplingSignal TransductionT cell regulationT-Cell ActivationT-Cell DevelopmentT-LymphocyteTestingTreatment EfficacyTumor EscapeTumor ImmunityTumor-DerivedUp-Regulationaerobic glycolysisbasecancer cellcancer immunotherapycancer therapyclinical translationcombinatorialeffector T cellexhaustionfatty acid metabolismfatty acid oxidationfrontierimmune checkpointimmune functionimmunoregulationimmunotherapy clinical trialsimprovedin vivoinhibitormelanomametabolic fitnessmetabolomicsneoplastic cellnovelnovel strategiesoverexpressionpotential biomarkerpredicting responsepressureresponsetumortumor microenvironmentubiquitin-protein ligase
项目摘要
PROJECT SUMMARY
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. Unfortunately, tumor reactive T cells often display a compromised
metabolic status due to metabolic competition with cancer cells within the tumor microenvironment (TME).
Therefore, strategies to enhance metabolic fitness of T cells within the metabolically challenging tumor bed
may rescue resistance to existing cancer immunotherapies. In this context, we have focused on the regulation
of T cell metabolism by Sirt2, an NAD-dependent histone deacetylase. Our preliminary data demonstrate that
Sirt2 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 glycolysis and oxidative-phosphorylation by deacetylating key metabolic
enzymes. Accordingly, Sirt2-deficient T cells manifest increased glycolysis and oxidative-phosphorylation,
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 targeting Sirt2 may allow reprogramming of T cell metabolism to
augment a broad spectrum of cancer immunotherapies. Guided by this scientific premise we propose the
overall hypothesis that Sirt2 activity governs the metabolic fitness of T cells at tumor beds, and
therefore controls the magnitude of immune pressure against malignant progression. We will test this
hypothesis in the following specific aims: Aim 1 will investigate the precise molecular mechanisms via which
Sirt2 regulate glycolysis, TCA cycle, glutaminolysis and fatty acid oxidation, and the post-translational
mechanisms that govern Sirt2 expression and function in tumor-reactive T cells. Aim 2 will explore the
metabolic functions of Sirt2 in physiologic contexts of T cells during activation, differentiation, maturation and
as they are subjected to metabolic constraints within the tumor beds. Aim 3 will determine the metabolic and
immunologic consequences of Sirt2 inhibition in human TILs for clinical translation, and correlate Sirt2
expression in TILs with response to immunotherapy. These aims will be achieved by employing a variety of
experimental strategies involving in vitro and in vivo metabolic and immunologic analyses of various genetically
engineered animals, complemented by molecular biology and genetic studies using primary human T cells and
patient-derived TILs from lung cancer and melanoma. Collectively, our proposed studies will provide a
comprehensive view of the role of Sirt2-regulated metabolic processes in tumor-reactive T cells. The results
from our proposed studies will validate Sirt2 as an actionable metabolic and immunologic target, and Sirt2
inhibition will be a tractable means to improve cancer immunotherapy.
项目总结
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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Sungjune Kim其他文献
Sungjune Kim的其他文献
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