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.

项目摘要 该项目的目的是定义控制T淋巴细胞代谢功能的调节网络 在体内稳态条件下和癌症的背景下。具体来说，我们旨在确定差异 不同的T细胞谱系感知并响应营养和代谢物信号的机制稳定 状态（AIM 1）和癌症实验模型（AIM 2）。肿瘤浸润的T细胞适应肿瘤 微环境（TME）通过调节控制其分化的信号传导和表观遗传网络 和功能。与这个概念一致，T细胞可以通过改变TME的代谢条件来适应代谢条件 控制胆固醇和脂肪酸转运，合成和分解代谢的调节机制。批判性， 抗肿瘤效应T细胞和抑制性FOXP3+的生物能量需求的差异 调节性t（Treg）可能是其在TME中的相对丰度和功能的基础。但是， 这些独特的T细胞子集感知并响应肿瘤的代谢状态的机制是 理解不佳。我们假设在生理条件下和肿瘤设定核受体中 充当局部代谢微环境的传感器可以差异地影响Treg和 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方法来评估 细胞脂质稳态的关键调节剂的T细胞中性作用，肝X受体（LXR），一种固醇 - 活化的核受体。在初步研究中，我们发现Treg的生存，而不是效应T细胞是 丢失了NR1H2的单个副本，即编码B同工型LXR（LXRB）的基因受到严重损害。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 LXRB信号的代谢适应性要求。这种细胞类型特异性的代谢脆弱性使LXRB 对肿瘤中Treg细胞功能的治疗操纵的潜在靶标。而且，因为平衡 在TME中Treg的相反功能和效应T细胞之间决定了自适应抗的结果 肿瘤反应，对treg和效应T细胞感知和的差异机制的理解 响应环境线索来指导其代谢功能，可能为特定靶向提供新的途径 这些细胞在治疗环境中。因此，我们的研究有可能通过 加速对癌症患者免疫代谢干预的新型策略的发展。