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

• 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
• 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

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.

项目摘要/摘要 虽然检查点抑制剂和嵌合抗原受体(CAR)T细胞经历了广泛的研究， 释放免疫系统的肿瘤靶向能力的方法，这些治疗的机制 失败是激烈辩论的主题。在实体瘤的背景下，人们认为微环境是有害的， 排除T细胞和/或抑制其增殖或激活的能力。新陈代谢前体的缺乏， 最值得注意的是，葡萄糖被认为是抑制T细胞功能的物质。仍然有一个未得到满足的需求 更好地了解T细胞代谢及其对体内肿瘤的影响的途径以及调节的方法 这一代谢限制克服了T细胞的耗竭。 给定大量的初步数据，我们开发了一个使用初级T细胞来探索T细胞耗竭的模型系统 体外刺激的细胞。我们还确定了一种代谢机制，可以通过以下方式克服有限的糖酵解通量 利用另一种生物可利用的底物：果糖。此外，我们还优化了追踪方法 利用超极化磁共振(HP MR)检测体内和体外代谢的变化 实时新陈代谢。总之，这些方法为研究免疫代谢提供了一个平台 在体外和体内建立了黑色素瘤的同基因模型，这对未来的免疫治疗具有巨大的潜力。 这一创新方案的目标是利用我们的体外和体内模型来询问 T细胞。在目标1中，我们将探索T细胞在体内的代谢，以逆转力竭时糖酵解通量降低的趋势。 T细胞。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 用我们最新研制的Hp显微核磁共振和体内Hp磁共振研究T细胞的代谢 光谱成像(MRSI)。然后，我们将在Aim 3中将这种方法转化为荷瘤小鼠，在那里我们 将T细胞疗法和HP MRI结合起来治疗同基因黑色素瘤模型。 这项提议的首要目标是使用这些新陈代谢和代谢成像的新方法来 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 病人。