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Glycolysis and Glutaminase in CD8 T cell differentiation and anti-tumor immunity

CD8 T 细胞分化和抗肿瘤免疫中的糖酵解和谷氨酰胺酶

基本信息

批准号：
10305643
负责人：
Matthew Zachary Madden
金额：
$ 5.18万
依托单位：
VANDERBILT UNIVERSITY
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：
2020-01-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10305643
关键词：
Affect Antineoplastic Agents B-Cell Acute Lymphoblastic Leukemia CD19 gene CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cell Differentiation process Cell Survival Cell physiology Cells Cellular Metabolic Process Chronic Citric Acid Cycle Clinical Clinical Trials Complement Data Dose Enzymes Epigenetic Process Eragrostis Excision Failure Generations Glucose Glutamates Glutaminase Glutamine Glycolysis Glycolysis Inhibition Goals Housekeeping Immunotherapy Impairment Inflammation Inflammatory Interferon Type II Knock-out Lead Longevity Maintenance Malignant Neoplasms Measures Memory Metabolic Metabolism Mitochondria Modality Modeling Mus Oncology Outcome Oxidative Phosphorylation Pathway interactions Patients Phenotype Play Population Production Proliferating Reaction Regulation Reporting Role Solid Neoplasm T cell differentiation T memory cell T-Lymphocyte Testing Tumor Immunity Work aerobic glycolysis alpha ketoglutarate anti-PD1 antibodies anti-PD1 therapy anti-cancer anticancer activity cancer cell cancer immunotherapy cancer therapy chimeric antigen receptor T cells conditional knockout cytotoxic CD8 T cells demethylation effector T cell exhaustion glucose uptake immune checkpoint blockade immunoregulation improved in vivo inhibitor long term memory metabolic fitness metabolic phenotype mitochondrial metabolism mouse model novel strategies oxidation programs receptor response tumor tumor metabolism tumor progression tumorigenesis

项目摘要

Summary Immunotherapy has transformed cancer treatment and improved clinical outcomes, but it does not cure most patients. Treatments such as anti-PD1 monoclonal antibodies and chimeric antigen receptor (CAR) T cells function by boosting the activity of cancer-specific interferon gamma-producing Th1 CD4 T cells and cytotoxic CD8 T cells (CTL). Increased effector function, however, must be balanced with the ability of anti- cancer T cells to persist long-term. A key goal of immunotherapy is to enhance effector function while maintaining T cell longevity and memory. It is now clear from work in the Rathmell lab that effector T cells utilize high rates of glycolysis while memory cells utilize mitochondrial pathways. Here I propose to test cell metabolism as a means to enhance both effector and memory T cell populations in immunotherapy. T cells radically alter their metabolism upon activation and increase glycolysis and glutamine oxidation (glutaminolysis) to support differentiation, effector function, and eventual generation of long-term memory that depend on mitochondria. Modulation of T cell glutamine metabolism may augment the efficacy of immunotherapy by enhancing both T cell effector function or memory capacity. The Rathmell Lab has shown that the metabolic program aerobic glycolysis is essential for effector T cell (Teff) function in inflammation and in tumors. Glutaminolysis complements glycolysis to fuel T cells by converting glutamine to the tricarboxylic acid cycle intermediate alpha-ketoglutarate (aKG). Using a conditional knockout of the glutaminolysis enzyme Glutaminase (GLS), which converts glutamine to glutamate, and an inhibitor of GLS that is currently in clinical trials as an anti-cancer agent, we have found that inhibition of GLS leads to a compensatory increase in glycolysis that enhances Th1 and CTL Teff function and differentiation. In addition to increasing effector function, however, I found that GLS inhibition also increases expression of inhibitory receptors, and chronic GLS deficiency ultimately suppresses T cells. In contrast, transient GLS inhibition enhanced Teff function while also priming mitochondrial metabolism for a memory-like differentiation, and led to improved T cell persistence in vivo. In this proposal, I will test the hypothesis that transient GLS inhibition can augment Teff function and maintain T cell survival and memory to boost anti-cancer immunotherapy efficacy, whereas chronic GLS inhibition will drive compensatory glycolysis, terminal Teff differentiation, and exhaustion. I will: (1) Test how transient versus chronic GLS inhibition affects CTL fate by determining differences in memory T cell formation, assessing the contribution of compensatory glycolysis to Teff phenotypes, and establishing the mitochondrial consequences of GLS inhibition; and (2) Test the effect of GLS inhibition on the immunotherapy efficacy of CD19-targeted CAR T cells and anti-PD1 treatment. These studies will demonstrate a new approach to improve anti-cancer immunotherapy and highlight a strategy of using GLS inhibition to modulate T cell metabolism and differentiation.

概括免疫疗法改变了癌症治疗并改善了临床结果，但它并不能治愈大多数癌症患者。抗 PD1 单克隆抗体和嵌合抗原受体 (CAR) T 细胞等治疗通过增强癌症特异性干扰素 γ 产生 Th1 CD4 T 细胞的活性来发挥作用细胞毒性 CD8 T 细胞 (CTL)。然而，效应器功能的增加必须与抗效应能力相平衡。癌症T细胞能够长期存在。免疫疗法的一个关键目标是增强效应功能，同时维持 T 细胞的寿命和记忆力。 Rathmell 实验室的工作现在清楚地表明，效应 T 细胞利用高速率的糖酵解，而记忆细胞则利用线粒体途径。这里我建议测试cell 代谢作为增强免疫治疗中效应 T 细胞和记忆 T 细胞群的一种手段。 T细胞激活后从根本上改变其代谢并增加糖酵解和谷氨酰胺氧化（谷氨酰胺分解）支持分化、效应器功能和长期记忆的最终生成依赖于线粒体。 T 细胞谷氨酰胺代谢的调节可能会增强通过增强 T 细胞效应功能或记忆能力的免疫疗法。 Rathmell 实验室已经证明代谢程序有氧糖酵解对于炎症和炎症中效应 T 细胞 (Teff) 的功能至关重要在肿瘤中。谷氨酰胺分解通过将谷氨酰胺转化为三羧酸来补充糖酵解，为 T 细胞提供燃料酸循环中间体α-酮戊二酸（aKG）。使用谷氨酰胺分解酶的条件敲除谷氨酰胺酶（GLS），可将谷氨酰胺转化为谷氨酸，以及目前处于临床阶段的 GLS 抑制剂作为抗癌剂的试验中，我们发现抑制 GLS 会导致代偿性增加糖酵解增强 Th1 和 CTL Teff 功能和分化。除了增加效应器然而，我发现 GLS 抑制也会增加抑制性受体的表达，并且慢性 GLS 缺陷最终会抑制 T 细胞。相反，短暂的 GLS 抑制增强了 Teff 功能，同时还启动线粒体代谢以实现类似记忆的分化，并提高 T 细胞的持久性体内。在这个提案中，我将测试短暂的 GLS 抑制可以增强 Teff 功能的假设，并且维持 T 细胞存活和记忆以提高抗癌免疫治疗效果，而慢性 GLS 抑制将驱动代偿性糖酵解、终末 Teff 分化和衰竭。我将：（1）测试如何短暂与慢性 GLS 抑制通过确定记忆 T 细胞形成的差异来影响 CTL 命运，评估代偿性糖酵解对 Teff 表型的贡献，并建立线粒体 GLS 抑制的后果； (2)测试GLS抑制对免疫治疗效果的影响 CD19 靶向 CAR T 细胞和抗 PD1 治疗。这些研究将展示一种新方法改进抗癌免疫治疗并强调利用 GLS 抑制调节 T 细胞的策略代谢和分化。