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（由应用提供）：在生产性免疫响应期间，肿瘤抗原特异性T细胞将被激活，并产生介导肿瘤清除率的各种效应分子。但是，T细胞通常会在癌症期间的功能和反应性逐渐下降，并且如果没有正确的功能性T细胞，肿瘤将继续增长。该T细胞功能障碍或精疲力尽被认为是由于连续暴露于抗原而引起的，因此重复刺激将T细胞驱动到更深的无响应状态，在这种情况下，诸如增殖，细胞因子产生，细胞毒性能力等功能以及最终生存的功能丧失。目前正在开发的许多癌症治疗试图靶向T细胞中的途径，这将使它们从功能障碍状态并增强效应子功能。尽管使用这种方法的疗法具有前途，但尚不完全了解T细胞在癌症期间疲惫和/或功能失调的基础基础，并且对这一过程的清晰理解是必须克服的关键障碍，以便有效地设计新的抗癌治疗。该建议解决了这个问题。这是基于我们新颖的发现，在T细胞中，转录后代谢调节效应子功能，并且该过程受到给定微环境中其他细胞的营养竞争控制。我们发现，通过参与或脱离糖酵解途径，调节T细胞的细胞因子的文字后产生后，甘油醛-3-磷酸脱氢酶（GAPDH）。我们表明，活化的T细胞可以使用氧化物磷酸化（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，随着营养可用性的变化或共刺激性或生长因子信号的变化可能发生，GAPDH的表达方式是其在GAPDH中的作用，以至于其在GAPDH的函数中，其在Gapolic Enzyme中的表达方式是在Gabolic Enzyme中的作用。免疫调节因素。尽管Oxphos可以支持T细胞的存活和增殖，但只有糖酵解才能促进全部效应子状态。这些发现表明，葡萄糖（GLC）的可用性直接确定在收到激活信号后是否可以产生细胞因子。鉴于许多肿瘤也会引起糖酵解（WARBURG效应），我们假设在癌症期间经历功能损失的肿瘤浸润的T细胞可能会导致肿瘤引起的GLC限制。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，即肿瘤对T细胞施加了GLC限制，该T细胞使T细胞的糖酵解和产生效应子细胞因子的能力。我们的实验将确定肿瘤微环境是否对肿瘤浸润的T细胞是营养限制性的，以及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）和控制肿瘤生长。我们希望通过完成我们的目标，我们将通过操纵代谢途径来开发新的治疗方法来逆转癌症的免疫功能障碍。