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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

基本信息

批准号：
9151813
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
项目类别：
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/9151813
关键词：
Address Antigens Back Binding Binding Proteins Cell Proliferation Cell Survival Cell physiology Cells Cellular Metabolic Process Coupled Data Defect Development Enzymes Event Exposure to Functional disorder Gene Expression Glucose Glyceraldehyde-3-Phosphate Dehydrogenases Glycolysis Glycolysis Pathway Growth 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 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 metabolic phenotype neoplastic cell novel prevent programs receptor research study sarcoma transcriptome sequencing tumor tumor growth tumor microenvironment tumor progression

项目摘要

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.