Metabolic reprogramming of Tregs in tumor immunity

肿瘤免疫中 Tregs 的代谢重编程

基本信息

批准号：
9403804
负责人：
Hongbo Chi
金额：
$ 41.06万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9403804
关键词：
Activated Lymphocyte Antigens Autoimmune Diseases Biochemical Biological Assay Cancer Cell Growth Cells Cellular Metabolic Process Cholesterol Homeostasis Colon Adenocarcinoma Colorectal Cancer Cytotoxic T-Lymphocyte-Associated Protein 4 Disease Enzymes FOXP3 gene FRAP1 gene Fatty Acids Genetic study Goals Growth Homeostasis Immune Immune Tolerance Immune response Immune signaling Immunity Immunosuppressive Agents Immunotherapy Lead Link Lipids Lymphocyte MC38 Maintenance Malignant Neoplasms Mediating Metabolic Metabolic Control Metabolic Pathway Metabolism Mitochondria Modeling Monomeric GTP-Binding Proteins Mus Oxidative Phosphorylation PDCD1LG1 gene Pathway interactions Play Process Program Description Regulation Regulatory T-Lymphocyte Respiration Role SCAP protein Signal Transduction T-Lymphocyte Testing Therapeutic Therapeutic Effect Tumor Immunity Warburg Effect aerobic glycolysis cancer cell cancer immunotherapy combat cytokine immune checkpoint blockade immunogenic immunoregulation innovation insight lipid biosynthesis melanoma metabolomics mevalonate mitochondrial metabolism mtTF1 transcription factor neoplastic cell novel prevent programs stable isotope tool transcription factor tumor tumor microenvironment

Activated Lymphocyte Antigens Autoimmune Diseases Biochemical Biological Assay Cancer Cell Growth Cells Cellular Metabolic Process Cholesterol Homeostasis Colon Adenocarcinoma Colorectal Cancer Cytotoxic T-Lymphocyte-Associated Protein 4 Disease Enzymes FOXP3 gene FRAP1 gene Fatty Acids Genetic study Goals Growth Homeostasis Immune Immune Tolerance Immune response Immune signaling Immunity Immunosuppressive Agents Immunotherapy Lead Link Lipids Lymphocyte MC38 Maintenance Malignant Neoplasms Mediating Metabolic Metabolic Control Metabolic Pathway Metabolism Mitochondria Modeling Monomeric GTP-Binding Proteins Mus Oxidative Phosphorylation PDCD1LG1 gene Pathway interactions Play Process Program Description Regulation Regulatory T-Lymphocyte Respiration Role SCAP protein Signal Transduction T-Lymphocyte Testing Therapeutic Therapeutic Effect Tumor Immunity Warburg Effect aerobic glycolysis cancer cell cancer immunotherapy combat cytokine immune checkpoint blockade immunogenic immunoregulation innovation insight lipid biosynthesis melanoma metabolomics mevalonate mitochondrial metabolism mtTF1 transcription factor neoplastic cell novel prevent programs stable isotope tool transcription factor tumor tumor microenvironment

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项目摘要

Program Description/Abstract Metabolic reprogramming is a fundamental process underlying the growth of cancer cells and activated lymphocytes. These rapidly dividing cells markedly upregulate aerobic glycolysis (Warburg metabolism) and also reprogram mitochondrial oxidative phosphorylation (OXPHOS) to support the energy and growth demands. Moreover, mTOR signaling is a central regulator of anabolic metabolism in cancer cells and lymphocytes. While Warburg and mitochondrial metabolism and mTOR signaling are being actively studied, we are just beginning to appreciate the involvement of other biosynthetic programs such as de novo lipid synthesis (lipogenesis). Emerging evidence highlights that cancer immunotherapy is a powerful tool to combat cancers, but immune tolerance mediated by immunosuppressive regulatory T cells (Tregs) represents a major obstacle for effective anti-tumor immunity. Although mTOR was generally considered a crucial negative regulator of Tregs, our genetic studies have revealed that mTORC1 is a pivotal positive determinant of Treg function by linking immune signals to the lipogenic program. In our preliminary studies, disruption of the lipogenic program in Tregs rendered the mice to reject tumor cells but did not cause obvious autoimmune disorders under steady state. We hypothesize that lipogenic program contributes to Treg suppressive activity in the tumor microenvironment, which could represent a novel target for cancer immunotherapy. We will test this hypothesis by establishing the roles of Treg lipogenic programs in tumor immunity, and determining the metabolic and signaling basis whereby lipogenesis programs Treg functions. We predict these studies will establish a new paradigm on our understanding of lipogenic program in Tregs and how this impinges upon tumor immunity. Insights gained from this project will likely lead to innovative strategies on cancer immunotherapy by capitalizing on metabolic reprogramming of Tregs.

程序说明/摘要代谢重编程是癌细胞生长并激活的基本过程淋巴细胞。这些快速分裂的细胞明显上调有氧糖酵解（Warburg代谢）和还要重编程线粒体氧化磷酸化（OXPHOS）以支持能量和生长需求。此外，mTOR信号传导是癌细胞和淋巴细胞。尽管正在积极研究Warburg和线粒体代谢和MTOR信号传导时，我们刚刚开始欣赏其他生物合成程序的参与，例如从头脂质合成（脂肪生成）。新兴的证据表明，癌症免疫疗法是对抗癌症的强大工具，但是免疫抑制调节T细胞（TREG）介导的免疫耐受性代表了主要障碍有效的抗肿瘤免疫。尽管MTOR通常被认为是关键的负调节剂 Tregs，我们的遗传研究表明，MTORC1是Treg功能的关键阳性决定因素将免疫信号与脂肪生成程序联系起来。在我们的初步研究中，脂肪源计划的破坏在Treg中，小鼠拒绝肿瘤细胞，但并未在稳定下引起明显的自身免疫性疾病状态。我们假设脂肪生成计划有助于肿瘤中的Treg抑制活性微环境可以代表癌症免疫疗法的新靶标。我们将检验这个假设通过确定Treg脂肪生成计划在肿瘤免疫中的作用，并确定代谢和信号基础脂肪形成程序Treg功能。我们预测这些研究将建立一个新的关于我们对Treg中脂肪生成程序的理解以及这如何影响肿瘤免疫力的范式。从该项目中获得的见解可能会导致有关癌症免疫疗法的创新策略利用Treg的代谢重编程。