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: 8759445
• 负责人: Erika L Pearce
• 金额: $ 31.64万
• 依托单位: WASHINGTON UNIVERSITY
• 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 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8759445
• 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; 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; base; cancer cell; cancer therapy; cytokine; cytotoxic; design; exhaust; exhaustion; experience; functional decline; in vivo; loss of function; neoplastic cell; novel; prevent; programs; public health relevance; receptor; research study; sarcoma; 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）：在有效的免疫反应期间，幼​​稚肿瘤抗原特异性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，在癌症过程中，T 细胞的功能和反应能力通常会逐渐下降，如果 T 细胞功能不正常，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，这样重复的刺激就会促使T细胞进入更深的无反应状态，其中增殖、细胞因子产生、细胞毒性能力和最终生存等功能都丧失。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 T 细胞在癌症过程中耗尽和/或功能失调的根本原因尚未完全了解，并且对这一过程的清晰了解是有效设计新的抗癌疗法必须克服的关键障碍。本提案解决了这个问题。它基于我们的新发现，即 T 细胞代谢在转录后调节效应子功能，并且该过程是通过与其他细胞在给定微环境中对营养物质的竞争来控制的。 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 T 细胞转录后产生细胞因子。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，但是当 T 细胞在这些 ATP 生成程序之间切换时（如营养可用性或共刺激或生长因子信号的变化），GAPDH 从其作为糖酵解中的代谢酶的功能转变为作为控制 ATP 表达的 RNA 结合蛋白的功能。 免疫调节因素。因此，虽然 OXPHOS 可以支持 T 细胞存活和增殖，但只有糖酵解才能促进完全效应状态。这些发现表明，葡萄糖 (Glc) 的可用性直接决定 T 细胞在收到激活信号后是否能够产生细胞因子。鉴于许多肿瘤也参与糖酵解（Warburg 效应），我们推测在癌症期间经历功能丧失的肿瘤浸润 T 细胞可能是由于肿瘤施加的 Glc 限制而导致功能丧失。为了测试这一点，我们使用了体外方法和体内肉瘤模型，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 T 细胞存在营养限制，以及 T 细胞是否无法参与 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提供重要知识，通过操纵代谢途径来逆转癌症中的免疫功能障碍。