The Role of Metabolite Sensing in T cell Homeostasis and Tumor Immunology

代谢物传感在 T 细胞稳态和肿瘤免疫学中的作用

• 批准号: 10223175
• 负责人: Anthony Michaels
• 金额: $ 4.6万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10223175
• 关键词: Ablation; Affect; Agonist; Alleles; Antitumor Response; Bioenergetics; Bone Marrow; Cancer Model; Cancer Patient; Catabolism; Cell Lineage; Cell Survival; Cell physiology; Cells; Chimera organism; Cholesterol; Clinical; Cues; Development; Epigenetic Process; Equilibrium; Exhibits; Experimental Models; FOXP3 gene; Fatty Acids; Functional disorder; Gene Dosage; Gene Expression; Gene Proteins; Genes; Genetic; Goals; Homeostasis; Immune; Impairment; Implant; Inflammatory; Intervention; Isogenic transplantation; LXRalpha protein; Lead; Lipids; Liver X Receptor; Lymphopenia; Malignant Neoplasms; Measurement; Mediating; Metabolic; Metabolic Control; Metabolism; Mitochondria; Mus; Myeloid Cells; Neoplasm Transplantation; Nuclear Receptors; Nutrient; Outcome; Output; Patients; Pharmacology; Phenotype; Physiological; Protein Biosynthesis; Protein Isoforms; Proteome; Publishing; Receptor Activation; Regulation; Regulatory T-Lymphocyte; Reporting; Research; Resistance; Role; Signal Transduction; Spatial Distribution; Sterols; T cell differentiation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Therapeutic Intervention; Tumor Immunity; Tumor stage; autoimmune inflammation; cell type; cholesterol control; clinical care; early onset; effector T cell; fatty acid transport; fitness; immune activation; immune function; immunoregulation; improved; lipid metabolism; lipidome; liver function; metabolic fitness; mouse model; mutant; novel; novel strategies; preference; ribosome profiling; sensor; success; targeted treatment; transcriptome sequencing; tumor; tumor growth; tumor immunology; tumor microenvironment; uptake

Project Summary The goal of this project is to define the regulatory networks that control the metabolic function of T lymphocytes under homeostatic conditions and in the context of cancer. Specifically, we aim to identify the differential mechanisms by which distinct T cell lineages sense and respond to nutrient and metabolite signals at steady state (Aim 1) and in experimental models of cancer (Aim 2). Tumor-infiltrating T cells adapt to the tumor microenvironment (TME) by modulating the signaling and epigenetic networks that control their differentiation and function. In line with this notion, T cells can acclimate to metabolic conditions in the TME by altering regulatory mechanisms controlling cholesterol and fatty acid transport, synthesis, and catabolism. Critically, differences in the bioenergetic requirements of antitumor effector T cells and those of suppressive FOXP3+ regulatory T (Treg) may underlie their relative abundance and functionality in the TME. However, the mechanisms by which these distinct T cell subsets sense and respond to the metabolic status of the tumor are poorly understood. We hypothesize that under physiologic conditions and in the tumor setting nuclear receptors serving as sensors of the local metabolic microenvironment can differentially affect the functionality of Treg and effector T cells. To test this hypothesis, we will use targeted genetic and pharmacologic approaches to assess the T cell-intrinsic role of a critical regulator of cellular lipid homeostasis, the liver X receptor (LXR), a sterol- activated nuclear receptor. In preliminary studies, we found that the survival of Treg, but not effector T cells is critically impaired by loss of a single copy of Nr1h2, the gene encoding b isoform of LXR (LXRb). The relative sensitivity of Treg cells to Nr1h2 gene dosage leads us to predict that Treg and effector T cells exhibit differential requirements for LXRb signaling for metabolic fitness. This cell type-specific metabolic vulnerability makes LXRb a potential target for therapeutic manipulation of Treg cell function in tumors. Moreover, because the balance between opposing functions of Treg and effector T cells in the TME determines the outcome of the adaptive anti- tumor response, an understanding of the differential mechanisms by which Treg and effector T cells sense and respond to environmental cues to direct their metabolic function may provide novel avenues for specific targeting of these cells in therapeutic settings. Therefore, our research has the potential to improve clinical care by accelerating the development of novel strategies for immunometabolic intervention in cancer patients.

项目概要 该项目的目标是定义控制 T 淋巴细胞代谢功能的调控网络 在稳态条件下和癌症背景下。具体来说，我们的目标是识别差异 不同 T 细胞谱系在稳定状态下感知和响应营养和代谢信号的机制 状态（目标 1）和癌症实验模型（目标 2）。肿瘤浸润 T 细胞适应肿瘤 通过调节控制其分化的信号传导和表观遗传网络来微环境（TME） 和功能。根据这一概念，T 细胞可以通过改变 TME 中的代谢条件来适应 控制胆固醇和脂肪酸运输、合成和分解代谢的调节机制。关键的是， 抗肿瘤效应 T 细胞和抑制性 FOXP3+ 生物能需求的差异 调节性 T (Treg) 可能是其在 TME 中相对丰度和功能的基础。然而， 这些不同的 T 细胞亚群感知和响应肿瘤代谢状态的机制是 不太了解。我们假设在生理条件下和在肿瘤环境中核受体 作为局部代谢微环境的传感器可以对 Treg 和 Treg 的功能产生不同的影响 效应T细胞。为了检验这一假设，我们将使用有针对性的遗传和药理学方法来评估 细胞脂质稳态的关键调节剂肝脏 X 受体 (LXR)（一种甾醇）的 T 细胞内在作用 激活的核受体。在初步研究中，我们发现 Treg 细胞而非效应 T 细胞的存活率 Nr1h2 的单个拷贝的丢失导致严重受损，Nr1h2 是编码 LXR (LXRb) b 亚型的基因。亲戚 Treg 细胞对 Nr1h2 基因剂量的敏感性使我们预测 Treg 和效应 T 细胞表现出差异 代谢适应性对 LXRb 信号传导的要求。这种细胞类型特异性的代谢脆弱性使得 LXRb 肿瘤中 Treg 细胞功能的治疗操作的潜在靶点。此外，由于平衡 TME 中 Treg 和效应 T 细胞的相反功能决定了适应性抗- 肿瘤反应，了解 Treg 和效应 T 细胞感知和 响应环境线索来指导其代谢功能可能为特定目标提供新途径 这些细胞在治疗环境中的变化。因此，我们的研究有潜力通过以下方式改善临床护理： 加速开发癌症患者免疫代谢干预的新策略。