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: 10445240
• 负责人: Anthony Michaels
• 金额: $ 4.68万
• 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/10445240
• 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 本项目的目标是确定控制T淋巴细胞代谢功能的调节网络 在体内平衡的条件下和在癌症的背景下。具体来说，我们的目标是确定差异 不同的T细胞谱系感知和响应稳定的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）。肿瘤浸润性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， 和功能根据这一观点，T细胞可以通过改变TME中的代谢条件来适应TME中的代谢条件。 控制胆固醇和脂肪酸转运、合成和代谢的调节机制。重要的是， 抗肿瘤效应T细胞和抑制性FOXP 3+细胞的生物能量需求的差异 调节性T（Treg）可能是它们在TME中的相对丰度和功能性的基础。但 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肿瘤环境中， 作为局部代谢微环境的传感器可以不同地影响Treg的功能， 效应T细胞。为了验证这一假设，我们将使用靶向遗传学和药理学方法来评估 细胞脂质稳态的关键调节因子肝脏X受体（LXR），一种固醇， 激活核受体在初步研究中，我们发现Treg细胞的存活，而不是效应T细胞的存活， 严重受损的单拷贝的Nr 1h 2，基因编码B亚型的LXR（LXRb）的损失。的相对 Treg细胞对Nr 1h 2基因剂量的敏感性使我们预测Treg和效应T细胞表现出差异性， LXRb信号传导对代谢适应性的要求。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标。此外，由于平衡 在TME中Treg和效应T细胞的相反功能之间的相互作用决定了适应性抗- 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它们的代谢功能可能为特异性靶向提供新的途径 这些细胞在治疗环境中的作用。因此，我们的研究有可能通过以下方式改善临床护理： 加速癌症患者免疫代谢干预新策略的开发。