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

项目摘要 该项目的目标是定义控制T淋巴细胞代谢功能的调节网络 在动态平衡条件下和在癌症的背景下。具体地说，我们的目标是识别差异 不同T细胞系稳定感知和响应营养和代谢物信号的机制 状态(目标1)和癌症实验模型(目标2)。肿瘤浸润性T细胞对肿瘤的适应性 微环境(TME)通过调节控制其分化的信号和表观遗传网络 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TME的代谢条件 控制胆固醇和脂肪酸运输、合成和分解代谢的调控机制。关键是， 抗肿瘤效应T细胞和抑制FOXP3细胞对生物能量需求的差异 调节性T(Treg)可能是它们在TME中相对丰富和功能的基础。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 人们对此知之甚少。我们假设在生理条件下和在肿瘤中设置核受体 作为局部代谢微环境的传感器，可以不同地影响Treg和 效应器T细胞。为了验证这一假设，我们将使用有针对性的遗传和药理学方法来评估 肝X受体(LXR)是一种重要的细胞脂平衡调节器，它是一种类固醇受体，在T细胞中扮演着重要的角色。 激活的核受体。在初步研究中，我们发现Treg细胞的存活，但不是效应T细胞 由于编码LXR(LXRb)b亚型的基因Nr1h2的单个拷贝丢失而严重受损。相对的 Treg细胞对Nr1h2基因剂量的敏感性使我们预测Treg和效应器T细胞表现出差异 新陈代谢适应性对LXRb信号的要求。这种特定细胞类型的代谢脆弱性使LXRb 肿瘤Treg细胞功能治疗的潜在靶点。此外，因为余额 TME中Treg和效应性T细胞的相对功能之间的关系决定了适应性抗-T细胞治疗的结果 肿瘤反应，对Treg和效应器T细胞感知和 对环境信号的反应来指导它们的代谢功能可能为特定靶向提供新的途径 在治疗环境中的这些细胞。因此，我们的研究有可能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。

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.