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.

项目总结/摘要 虽然检查点抑制剂和嵌合抗原受体（CAR）T细胞作为免疫抑制剂进行了广泛的研究， 释放免疫系统肿瘤靶向能力的方法，这些疗法的机制 失败是一个大辩论的主题。在实体瘤的情况下，认为微环境是不利的， 排除T细胞和/或抑制其增殖或被激活的能力。缺乏代谢前体， 最显著的是葡萄糖，被认为抑制T细胞功能。仍然有一个未满足的需要， 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T细胞代谢的方法。 这种代谢限制来克服T细胞衰竭。 鉴于广泛的初步数据，我们已经开发了一个模型系统，以探讨T细胞耗竭使用原代T细胞， 体外刺激的细胞。我们还确定了一种代谢机制，可以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，我们还优化了跟踪方法， 使用超极化磁共振（HP MR）进行体外和体内代谢，可以检测 真实的新陈代谢。总之，这些方法为研究免疫代谢提供了平台， 在体外和体内在黑色素瘤的同基因模型中，其在未来的免疫治疗中具有很大的潜力。 这项创新建议的目的是利用我们的体外和体内模型来询问代谢的 T细胞。在目标1中，我们将探索体内T细胞代谢，以逆转耗尽的糖酵解通量降低。 T细胞。在目标2中，利用我们新开发的HP果糖，我们将代谢成像果糖 使用我们新开发的HP microNMR和HP磁共振在体内研究T细胞代谢 光谱成像（MRSI）。然后，我们将把这种方法转化为目标3中的荷瘤小鼠， 联合收割机T细胞疗法和HP MRI治疗同系黑色素瘤模型。 本提案的首要目标是在代谢和代谢成像中使用这些新方法， 进一步了解免疫代谢，并为未来的免疫治疗策略奠定基础， 患者