Role of Sirt2 in T Cell Metabolism

Sirt2 在 T 细胞代谢中的作用

• 批准号: 10898140
• 负责人: Sungjune Kim
• 金额: $ 17.76万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 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 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10898140
• 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.

项目总结 新陈代谢是T细胞功能的关键驱动因素，也是从氧化-磷酸化向有氧转换的关键 糖酵解是T细胞活化的标志。不幸的是，肿瘤反应性T细胞通常表现为 由于在肿瘤微环境(TME)内与癌细胞的代谢竞争而导致的代谢状态。 因此，在具有代谢挑战性的肿瘤床内增强T细胞代谢适合性的策略 可能会挽救对现有癌症免疫疗法的耐药性。在这种背景下，我们把重点放在了监管上 SIRT2对T细胞代谢的影响，SIRT2是一种依赖NAD的组蛋白脱乙酰基酶。我们的初步数据表明 SIRT2作为代谢检查点发挥作用，利用T细胞效应器功能并削弱抗肿瘤作用 豁免权。具体地说，上调人肿瘤浸润性T淋巴细胞(TIL)中SIRT2的表达 非小细胞肺癌患者对Nivolumab和TIL治疗的反应呈负相关。 从机制上讲，SIRT2通过去乙酰化关键代谢抑制糖酵解和氧化-磷酸化 酵素。相应地，缺乏SIRT2的T细胞表现出糖酵解和氧化磷酸化增加， 表现出增强的增殖和效应功能，并具有优越的抗肿瘤活性。重要的是 SIRT2的药物抑制赋予人TIL这些优越的代谢适应性和增强 效应器功能。这些发现表明，靶向SIRT2可能允许T细胞代谢重新编程以 加强广泛的癌症免疫疗法。在这一科学前提的指导下，我们提出 总体假设SIRT2活性控制肿瘤床上T细胞的新陈代谢适合性，以及 从而控制免疫压力的大小，防止恶性进展。我们将对此进行测试 以下具体目标中的假设：目标1将研究通过以下机制的确切分子机制 SIRT2调节糖酵解、TCA循环、谷氨酰胺分解和脂肪酸氧化，以及翻译后 肿瘤反应性T细胞中SIRT2表达和功能的调控机制。Aim 2将探索 SIRT2在T细胞活化、分化、成熟和成熟生理环境中的代谢功能 因为它们在肿瘤床内受到新陈代谢的限制。目标3将决定新陈代谢和 抑制人类TIL中SIRT2的免疫学后果及其与SIRT2的相关性 免疫治疗后TIL的表达。这些目标将通过使用各种不同的 涉及不同基因的体内外代谢和免疫学分析的实验策略 基因工程动物，辅以分子生物学和遗传学研究，使用原代人类T细胞和 患者从肺癌和黑色素瘤中提取的TIL。总的来说，我们建议的研究将提供一个 综述SIRT2调节的代谢过程在肿瘤反应性T细胞中的作用。结果是 我们建议的研究将验证SIRT2作为一个可操作的代谢和免疫学靶点，以及SIRT2 抑制将是改善癌症免疫治疗的一种容易掌握的手段。