Leveraging fructose transport to create a privileged substrate to selectively fuel T cells

利用果糖运输创造一种特殊底物来选择性地为 T 细胞提供燃料

基本信息

批准号：
10318220
负责人：
Kayvan R Keshari
金额：
$ 70.44万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-11 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10318220
关键词：
Address Animal Model Biochemistry Biological Availability Biological Models Cancer Biology Carbon Cell physiology Cellular Metabolic Process Charge Clinic Data Diet Dietary Component Effectiveness Energy Metabolism Engineering Enzymes Exhibits Foundations Fructose Future GLUT-2 protein Gluconeogenesis Glucose Glucose Transporter Glycolysis Goals Image Immune checkpoint inhibitor Immune system Immunotherapeutic agent Immunotherapy In Vitro Insulin Investigation Isotopes Ketohexokinase Kidney Liver Magnetic Resonance Magnetic Resonance Imaging Malignant Neoplasms Measures Mediating Metabolic Metabolism Methods Modeling Monosaccharides Motivation Mus Nutrient Oxygen Pathway interactions Patients Production Proliferating Research Serine Small Intestines Solid Neoplasm System T cell therapy T-Lymphocyte Technology Time Tissues Translating Translations Warburg Effect Work base cancer biomarkers cancer cell cancer immunotherapy checkpoint inhibition chimeric antigen receptor T cells effector T cell engineered T cells exhaust exhaustion extracellular fructose-1-phosphate imaging approach immune checkpoint blockade in vivo in vivo Model innovation liquid chromatography mass spectrometry magnetic resonance spectroscopic imaging melanoma metabolic imaging metabolomics neoplastic cell new technology non-invasive imaging novel novel strategies overexpression response sugar tool trafficking tumor tumor microenvironment

项目摘要

PROJECT SUMMARY/ABSTRACT While checkpoint inhibitors and chimeric antigen receptor (CAR) T cells undergo widespread investigation as approaches to unleash the immune system’s tumor-targeting abilities, the mechanisms by which these therapies fail is the subject of great debate. In the setting of solid tumors, it is believed that the microenvironment is hostile, excluding T cells and/or inhibiting their ability to proliferate or be activated. A dearth of metabolic precursors, most notably glucose, has been implicated as inhibiting T-cell function. There remains an unmet need for approaches to better understand T-cell metabolism and its impact on tumors in vivo, as well as a method to modulate this metabolic limitation to overcome T-cell exhaustion. Given extensive preliminary data, we have developed a model system to explore T-cell exhaustion using primary T cells stimulated in vitro. We have also identified a metabolic mechanism that can overcome limited glycolytic flux by utilizing another biologically available substrate: fructose. Moreover, we have optimized methods to trace metabolism in vitro and in vivo using hyperpolarized magnetic resonance (HP MR), which can detect changes in metabolism in real time. Taken together, these approaches provide a platform for studying immunometabolism both in vitro and in vivo in a syngeneic model of melanoma, which has great potential for future immunotherapeutics. The objective of this innovative proposal is to utilize our in vitro and in vivo models to interrogate the metabolism of T cells. In Aim 1, we will explore T-cell metabolism in vivo in order to reverse the reduced glycolytic flux in exhausted T cells. In Aim 2, taking advantage of our newly developed HP fructose, we will metabolically image fructose metabolism in T cells using our newly developed HP microNMR and in vivo with HP magnetic resonance spectroscopic imaging (MRSI). We will then translate this approach to tumor-bearing mice in Aim 3, where we combine T-cell therapy and HP MRI to treat a syngeneic model of melanoma. It is the overarching goal of this proposal to use these novel approaches in metabolism and metabolic imaging to further our understanding of immunometabolism and lay the foundation for future immunotherapy strategies in patients.

项目概要/摘要虽然检查点抑制剂和嵌合抗原受体 (CAR) T 细胞正在接受广泛的研究，释放免疫系统肿瘤靶向能力的方法，这些疗法的机制在实体瘤的背景下，失败是一个大争论的话题，人们认为微环境是不利的，排除 T 细胞和/或抑制其增殖或激活的能力缺乏代谢前体，最值得注意的是葡萄糖，已被认为会抑制 T 细胞功能，但目前对葡萄糖的需求仍未得到满足。更好地了解 T 细胞代谢及其对体内肿瘤影响的方法，以及调节方法这种代谢限制可以克服 T 细胞的耗竭。鉴于广泛的初步数据，我们开发了一个模型系统，利用初级 T 细胞探索 T 细胞耗竭。我们还确定了一种代谢机制，可以克服有限的糖酵解通量。此外，我们还优化了追踪方法使用超极化磁共振 (HP MR) 进行体外和体内代谢研究，可检测总而言之，这些方法为研究免疫代谢提供了一个平台。在黑色素瘤同基因模型中进行体外和体内研究，这对于未来的免疫治疗具有巨大的潜力。这项创新提案的目的是利用我们的体外和体内模型来探究在目标 1 中，我们将探索体内 T 细胞代谢，以逆转精疲力尽时糖酵解通量的减少。在目标 2 中，利用我们新开发的 HP 果糖，我们将对果糖进行代谢成像。使用我们新开发的 HP microNMR 进行 T 细胞代谢，并使用 HP 磁共振进行体内代谢然后，我们将在目标 3 中将此方法转化为荷瘤小鼠。结合 T 细胞疗法和 HP MRI 来治疗黑色素瘤的同基因模型。该提案的总体目标是利用代谢和代谢成像中的这些新方法来进一步加深我们对免疫代谢的理解，为未来的免疫治疗策略奠定基础患者。