Role of Sirt2 in T Cell Metabolism

Sirt2 在 T 细胞代谢中的作用

• 批准号: 10576885
• 负责人: Sungjune Kim
• 金额: $ 19.16万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2023-06-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10576885
• 关键词: Acetylation; Aging; Animals; Attention; Beds; CTAG1 gene; Cancer Patient; Cell physiology; Cells; Cellular Metabolic Process; Citric Acid Cycle; Complement; Data; Deacetylase; Deacetylation; Development; Endowment; Enzymes; Genes; Genetic Engineering; Genetic study; Glucose; Glutamine; Glycolysis; Histone Deacetylase; Human; Human Engineering; Immune; Immune Targeting; Immune response; Immunologics; Immunotherapeutic agent; Immunotherapy; Impairment; In Vitro; Infiltration; Laboratories; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Memory; Metabolic; Metabolism; Modeling; Molecular; Molecular Biology; Molecular Genetics; Mus; Nivolumab; Non-Small-Cell Lung Carcinoma; Oxidative Phosphorylation; Patients; Phenotype; Phosphorylation; Physiological; Post-Translational Protein Processing; Proliferating; Protein Acetylation; Proteins; Proteomics; Reproducibility; Resistance; Resveratrol; Role; Sampling; Signal Transduction; T cell regulation; T-Cell Activation; T-Cell Development; T-Lymphocyte; Testing; Treatment Efficacy; Tumor Escape; Tumor Immunity; Up-Regulation; aerobic glycolysis; cancer cell; cancer immunotherapy; cancer therapy; clinical translation; combinatorial; effector T cell; exhaustion; fatty acid metabolism; fatty acid oxidation; frontier; immune checkpoint; immune function; immunoregulation; immunotherapy clinical trials; improved; in vivo; inhibitor; melanoma; metabolic fitness; metabolomics; neoplastic cell; novel; novel strategies; overexpression; pharmacologic; potential biomarker; predicting response; pressure; programs; response; tumor; tumor microenvironment; ubiquitin-protein ligase

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.

项目摘要 代谢是T细胞功能的关键驱动力，从氧化磷酸化到有氧代谢的转变是T细胞功能的关键驱动力。 糖酵解是T细胞活化的标志。不幸的是，肿瘤反应性T细胞通常表现出受损的免疫功能。 由于与肿瘤微环境（TME）内的癌细胞的代谢竞争而导致的代谢状态。 因此，增强T细胞在代谢挑战性肿瘤床内的代谢适应性的策略 可以挽救对现有癌症免疫疗法的抵抗力。在此背景下，我们重点关注了监管 Sirt 2是一种NAD依赖性组蛋白去乙酰化酶。我们的初步数据表明， Sirt 2作为代谢检查点发挥作用，利用T细胞效应器功能并损害抗肿瘤作用 免疫力具体而言，Sirt 2在人肿瘤浸润性T淋巴细胞（TIL）中表达的上调 与非小细胞肺癌中对Nivolumab和TIL治疗的反应呈负相关。 在机制上，Sirt 2通过使关键代谢产物脱乙酰化来抑制糖酵解和氧化磷酸化。 内切酶因此，Sirt 2缺陷型T细胞表现出糖酵解和氧化磷酸化增加， 显示增强的增殖和效应子功能，并具有上级抗肿瘤活性。重要的是， Sirt 2的药理学抑制赋予人TIL这些上级代谢适应性和增强的代谢适应性。 效应器功能。这些发现表明靶向Sirt 2可能允许T细胞代谢重编程， 扩大癌症免疫治疗的范围。在这一科学前提的指导下，我们提出 Sirt 2活性控制T细胞在肿瘤床的代谢适应性的总体假设， 因此控制了抵抗恶性进展的免疫压力的大小。我们将测试这个 假设有以下具体目标：目标1将研究精确的分子机制，通过该机制 Sirt 2调节糖酵解、TCA循环、β-氨基醇分解和脂肪酸氧化，以及翻译后的 在肿瘤反应性T细胞中控制Sirt 2表达和功能的机制。目标2将探讨 Sirt 2在T细胞活化、分化、成熟和分化过程中的生理环境中的代谢功能 因为它们在肿瘤床内受到代谢限制。目标3将确定代谢和 在人TIL中抑制Sirt 2用于临床翻译免疫学后果，以及相关的Sirt 2 在对免疫疗法有应答的TIL中的表达。这些目标将通过采用各种 实验策略包括体外和体内代谢和免疫分析的各种遗传 工程动物，辅之以使用原代人类T细胞的分子生物学和遗传学研究， 来自肺癌和黑色素瘤的患者来源的TIL。总的来说，我们提出的研究将提供一个 全面了解Sirt 2调节的代谢过程在肿瘤反应性T细胞中的作用。结果 将验证Sirt 2作为可操作的代谢和免疫靶点， 抑制将是改善癌症免疫治疗的一种易于处理的手段。