TUMOR-IMPOSED GLUCOSE RESTRICTIONS ON T CELLS DAMPEN IMMUNITY

肿瘤对 T 细胞施加的葡萄糖限制会削弱免疫力

• 批准号: 8913080
• 负责人: Erika L Pearce
• 金额: $ 22.41万
• 依托单位: INSTITUT FUR IMMUNBIOLOGIE/EPIGENETIK
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8913080
• 关键词: Address; Antigens; Back; Binding; Cell Proliferation; Cell Survival; Cell physiology; Cells; Coupled; Data; Defect; Development; Enzymes; Event; Exposure to; Functional disorder; Gene Expression; Glucose; Glyceraldehyde-3-Phosphate Dehydrogenases; Glycolysis; Glycolysis Pathway; Growth Factor; Health; Immune; Immune System Diseases; Immune response; Immune system; Immunity; In Vitro; Infection; Interferons; Knowledge; Lead; Link; Malignant Neoplasms; Mediating; Messenger RNA; Metabolic; Metabolic Pathway; Metabolism; Modeling; Mus; Nutrient; Oxidative Phosphorylation; Pathway interactions; Phenotype; Process; Production; Protein Binding; RNA-Binding Proteins; Regulation; Role; Signal Transduction; T-Lymphocyte; Testing; Translations; Tumor Antigens; Tumor Immunity; Warburg Effect; adaptive immunity; base; cancer cell; cancer therapy; cytokine; cytotoxic; design; exhaust; exhaustion; experience; functional decline; in vivo; loss of function; neoplastic cell; novel; prevent; programs; receptor; research study; sarcoma; transcriptome sequencing; tumor; tumor growth; tumor microenvironment; tumor progression

DESCRIPTION (provided by applicant): During a productive immune response na�ve tumor antigen-specific T cells will become activated and produce a variety of effector molecules that mediate tumor clearance. However, T cells often experience a progressive decline in function and responsiveness during cancer, and without properly functioning T cells, tumors will continue to grow. This T cell dysfunction, or exhaustion, is thought to result from continuous exposure to antigen, such that repetitive stimulation drives T cells into deeper states of unresponsiveness where functions such as proliferation, cytokine production, cytotoxic ability, and finally survival are lost. Many cancer treatments currently under development attempt to target pathways in T cells that will pull them back from their dysfunctional state and boost effector functions. While therapies using this approach hold promise, the underlying basis of why T cells become exhausted and/or dysfunctional during cancer is not completely understood and a clear understanding of this process is a critical barrier that must be overcome in order to effectively design new anti-cancer treatments. This proposal addresses this issue. It is based on our novel finding that in T cells metabolism posttranscriptionally regulates effector function and that this process is controlled by competition from other cells for nutrients in a given microenvironment. We found that the enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH), by engaging or disengaging the glycolysis pathway, regulates the posttranscriptional production of cytokines by T cells. We showed that activated T cells can use either oxidative phosphorylation (OXPHOS) or glycolysis to support proliferation and survival, but when T cells switch between these ATP generating programs, as can occur with changes in nutrient availability, or co-stimulatory or growth factor signals, GAPDH switches from its function as a metabolic enzyme in glycolysis to its function as an RNA binding protein controlling expression of immunomodulatory factors. Thus while OXPHOS can support T cell survival and proliferation, only glycolysis can facilitate full effector status. These findings showed that glucose (Glc) availability directly determines whether a T cell can produce cytokines after the receipt of activation signals. Given that many tumors also engage glycolysis (Warburg effect) we hypothesize that tumor-infiltrating T cells that experience a loss of function during cancer may do so as a result of tumor-imposed Glc restrictions. To test this we have used in vitro approaches and an in vivo sarcoma model and our preliminary data support that tumors impose Glc restrictions on T cells that dampens the T cell's ability to engage glycolysis and produce effector cytokines. Our experiments will establish whether the tumor microenvironment is nutrient-restrictive for tumor-infiltrating T cells, and whether the inability of T cells to engage glycolysis renders them unable to produce cytokines (via posttranscriptional mechanisms) and control tumor growth. We hope that by completing our aims we will provide crucial knowledge toward developing new treatments to reverse immune dysfunction in cancer through the manipulation of metabolic pathways.

描述（由申请人提供）：在有效的免疫反应过程中，天然肿瘤抗原特异性 T 细胞将被激活并产生多种介导肿瘤清除的效应分子。然而，T 细胞在此过程中通常会经历功能和反应性的逐渐下降。如果 T 细胞功能正常，肿瘤就会继续生长，这种 T 细胞功能障碍或衰竭被认为是由于持续暴露于抗原而导致的，这样重复的刺激会导致 T 细胞陷入更深的无反应状态，从而无法发挥增殖等功能。 , 细胞因子目前正在开发的许多癌症治疗方法都试图针对 T 细胞中的通路，将其从功能失调状态中拉回来并增强效应器功能，虽然使用这种方法的疗法有希望，但其根本基础是。为什么 T 细胞在癌症过程中变得疲惫和/或功能失调尚不完全清楚，为了有效地设计新的抗癌疗法，必须克服对这一过程的清晰理解。我们的新发现是 T 细胞转录后代谢调节效应器功能，并且该过程是通过在给定微环境中与其他细胞竞争营养物质来控制的。我们发现，3-磷酸甘油醛脱氢酶（GAPDH）通过参与或脱离糖酵解途径，调节细胞因子的转录后产生。我们发现，活化的 T 细胞可以使用氧化磷酸化 (OXPHOS) 或糖酵解来支持增殖和存活，但当 T 细胞在这些 ATP 生成之间切换时随着营养可用性、共刺激或生长因子信号的变化，GAPDH 从糖酵解中的代谢酶功能转变为控制免疫调节因子表达的 RNA 结合蛋白功能，因此 OXPHOS 可以支持。 T 细胞的存活和增殖，只有糖酵解才能促进完全效应状态。鉴于许多肿瘤也参与糖酵解，因此产生葡萄糖 (Glc) 的可用性直接决定 T 细胞是否可以产生细胞因子。效应）我们发现，在癌症期间经历功能丧失的肿瘤浸润性 T 细胞可能是由于肿瘤施加的 Glc 限制而导致的。为了测试这一点，我们使用了体外方法和体内肉瘤模型以及我们的初步数据。支持肿瘤对 T 细胞施加 Glc 限制，从而抑制 T 细胞参与糖酵解和产生效应细胞因子的能力。我们的实验将确定肿瘤微环境是否对肿瘤浸润性 T 细胞具有营养限制，以及是否存在营养限制。 T细胞无法参与 糖酵解使它们无法产生细胞因子（通过转录后机制）并控制肿瘤生长，我们希望通过完成我们的目标，我们将为开发新疗法以通过操纵代谢途径逆转癌症免疫功能障碍提供重要知识。