Uncovering the metabolic underpinnings of T cell exhaustion

揭示 T 细胞耗竭的代谢基础

• 批准号: 10593593
• 负责人: Greg M. Delgoffe
• 金额: $ 63.36万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10593593
• 关键词: Acetyl Coenzyme A; Aconitate Hydratase; Antigens; Antioxidants; Biology; Blocking Antibodies; Cell physiology; Cells; Cellular biology; Characteristics; Chronic; Citrates; Citric Acid Cycle; Cysteine; Cytosol; Data; Environment; Exposure to; Fatty Acids; Functional disorder; Genes; Genetic; Genetic Transcription; Glucose; Hypoxia; Immune; Immunity; Immunosuppression; Immunotherapy; In Vitro; Knockout Mice; Lipids; Lipolysis; Malignant Neoplasms; Mediating; Metabolic; Metabolic stress; Metabolism; Mitochondria; Modality; Modeling; Monoclonal Antibodies; Nutrient; Obesity; Oxidative Stress; Oxygen; PD-1 blockade; Pathway interactions; Patients; Peroxides; Pharmacology; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotyrosine; Play; Production; Protein Tyrosine Phosphatase; Proteome; Proteomics; Reactive Oxygen Species; Regulatory T-Lymphocyte; Reporting; Role; Signal Transduction; Source; Stress; T cell differentiation; T-Lymphocyte; Technology; Tissues; Tumor Immunity; Tumor-infiltrating immune cells; Tyrosine; Up-Regulation; Weight; anti-cancer; anti-tumor immune response; biological adaptation to stress; conditional knockout; cytokine; cytotoxic; cytotoxicity; design; exhaust; exhaustion; fatty acid oxidation; improved; in vivo; inhibitor; lipid biosynthesis; member; mitochondrial dysfunction; neoplastic cell; novel; novel therapeutics; overexpression; patient subsets; prevent; progenitor; programmed cell death protein 1; response; self-renewal; stress reactivity; success; transcriptomics; tumor growth; uptake

PROJECT SUMMARY/ABSTRACT The successes of immunotherapies like blockade of co-inhibitory `checkpoint' molecules have changed the treatment paradigm of cancer. However, the fact that robust responses are restricted to a subset of patients highlights the need to further understand the biology of exhausted T cells: what drives their differentiation, maintains their dysfunction, and how they may be reinvigorated to eradicate tumor cells. Our lab and others have revealed that metabolic stress and mitochondrial dysfunction are key drivers in T cell exhaustion, both from a cell extrinsic and cell intrinsic perspective. We recently reported that mitochondrial stress and reactive oxygen species (ROS) production, driven to intolerable levels under hypoxic environments in the face of persistent antigen, was sufficient to deviate cells into a terminally exhausted fate. Antioxidants both pharmacologic and genetic could bias T cell differentiation away from exhaustion to more functional fates. But precisely how ROS production alters T cell fate and function remains unclear. One of the more intriguing observations was elevating ROS via mitochondrial dysfunction altered T cell signaling: as peroxide is one of the more potent inhibitors of tyrosine phosphatases, elevating ROS alone mimicked TCR and other phosphotyrosine signals. ROS also dramatically reprograms cellular metabolism: by inhibiting aconitase, citrate is driven from the mitochondria where it is converted to acetyl-CoA, acting as a substrate for de novo lipogenesis. As a result, while exhausted cells possess dysfunctional mitochondria and compete poorly for glucose, they are loaded with lipid droplets and repress fatty acid oxidiation and lipolysis. While we know that mitochondrial stress can drive T cells to exhaustion and that terminally exhausted T cells are metabolically insufficient, the mechanisms that ultimately drive and enforce the phenotype remain unclear. In this Proposal, we will identify the metabolic underpinnings of T cell exhaustion: how metabolic stress can interfere with signaling, transcription, and differentiation. AIM 1: Determine how oxidative stress alters T cell signaling cascades at the level of phosphatase inhibition. ROS play central roles in signaling as inhibitors of tyrosine phosphatases. We will determine the role of ROS in exhausted T cell function in vivo, and use proteomics and transcriptomic technologies to identify the phosphorylation cascades susceptible to ROS induction. AIM 2: Identify how ROS-mediated changes in metabolic flux undermine T cell function. In this Aim, we will explore the role increased lipid storage plays in T cell function and ask whether these elevated levels of lipids represent `dead weight' or an untapped fuel source. AIM 3: Define the importance of altered nutrient pathways induced through oxidative stress responses. Our data suggest Slc16a11 similarly supports lactate uptake into exhausted T cells and maintains their dysfunctional state. Using a conditional knockout mouse and blocking antibodies, we will determine the importance of monocarboxylate metabolism in exhausted T cell biology.

项目总结/文摘