Immunometabolism in Cancer and Inflammation

癌症和炎症中的免疫代谢

• 批准号: 10925992
• 负责人: Daniel W. McVicar
• 金额: $ 263.99万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10925992
• 关键词: Acids; Advanced Malignant Neoplasm; Animal Model; Area; Ascites; Autologous; Biochemical Pathway; Biological Markers; Biology; CD4 Positive T Lymphocytes; Cancer Patient; Carbon; Cell Death; Cell physiology; Cells; Cellular Metabolic Process; Characteristics; Citrates; Coenzyme A; Complex; Development; Disease; Dissection; Environment; Enzymatic Biochemistry; Enzymes; Family; Fermentation; Foundations; Genes; Genetic Transcription; Glucose; Glycolysis; Goals; Greater sac of peritoneum; Hepatocyte; High Fat Diet; Host Defense Mechanism; Human; Immune; Immune response; Immunologics; Immunosuppression; Inflammation; Inflammatory; Investigation; Label; Leukocytes; Lipids; Liver; Macrophage; Macrophage Activation; Malignant Neoplasms; Mediating; Metabolic; Metabolic Control; Metabolic Diseases; Metabolic Pathway; Mitochondria; Modeling; Molecular Biology; Mus; Muscle; Myeloid Cells; Natural Killer Cells; Nature; Nitric Oxide; Nutritional Requirements; Obesity; Oxidative Phosphorylation; Palmitates; Patients; Peritoneal; Phosphoenolpyruvate; Phosphorylation; Physiological; Physiology; Play; Production; Proliferating; Pyruvate; Pyruvate Kinase; Renal carcinoma; Resources; Role; Signal Transduction; Source; Succinates; System; T-Cell Proliferation; T-Lymphocyte; Therapeutic; Time; Tumor Burden; Tumor Expansion; Tumor Promotion; Tumor-associated macrophages; Vascularization; Work; alpha ketoglutarate; cancer therapy; cell type; experimental study; feeding; glucose tolerance; immune modulating agents; insulin tolerance; interest; lipid metabolism; metabolomics; neoplastic cell; neutrophil; nonalcoholic steatohepatitis; oxidation; peritoneal cancer; programs; receptor; therapeutic target; tumor; tumor growth; tumor microenvironment; tumor progression

The tumor microenvironment represents a complex multicellular milieu where various cell types compete for the resources necessary for their function(s). Tumor cells promote the expansion of host vasculature to maintain sufficient levels of the nutrients required for their rapid proliferation. At the same time, tumor cells subjugate host defense mechanisms to thwart rejection. Many mechanisms of tumor-mediated immunosuppression have been described, and several target metabolic pathways. For example, highly glycolytic tumors deplete glucose in the microenvironment, suppressing T cell proliferation and activation. The resulting elevated lactate from the tumor can transcriptionally reprogram tumor-associated macrophages into immunosuppressive cells promoting tumor growth and progression. Taking these types of interactions into consideration, we view the tumor as a unique metabolic environment, or niche, within which the tumor cells and immune cells compete for resources and adapt to each other's presence. The aggressive nature of many cancers reflects the ability of tumors to exert a dominant role in this niche, subjugating the attempted immune response to facilitate tumor expansion, vascularization, and dissemination. This project is focused on understanding stimulation-induced alterations in cellular metabolic processes and the critical role that they play in enabling immune cells to meet the enhanced metabolic demands associated with activation. Thus, our work involves precise dissection of metabolic networks that govern immune cell function, as well as the investigation of the metabolic foundations of disease. Our work in this area has already provided us with exciting possibilities for unraveling, and possibly therapeutically exploiting, the substantial metabolic interactions between inflammatory cells and the tumor. In one aspect of this project, we found that a soluble version of Triggering Receptors Expressed on Myeloid cells (TREM)-1 is a biomarker in renal cancer. Our findings contribute to the role that the TREM family of receptors play in a variety of inflammatory diseases including cancer. Our work also defines the canonical role of pyruvate kinase muscle-2 (PKM2) in the metabolic control of Natural Killer (NK) cells and CD4+ T cells. As the penultimate enzyme of glycolysis, PKM converts phosphoenolpyruvate and ADP into ATP and pyruvate that is either fermented to lactate or imported into the mitochondria for oxidation. Our work has identified PKM2 as a central metabolic regulator of both NK and T cell function. In NK cells, the loss of PKM2 controlled cellular ROS levels and suppressed Myc signaling whereas in CD4+ T cells PKM2 controls pyruvate oxidation, and its absence leads to substantial oxidative cell death. These findings underscore the canonical function of PKM2 as a regulator of pyruvate utilization and contribute to the assignment of this metabolic pathway as a central regulator of NK and CD4+ T cell function. Our earlier work on the uniqueness of the peritoneal niche and its role in macrophage function, followed by our definition of neutrophil metabolic adaptations in cancer, have greatly refined our understanding on the metabolic adaptations that contribute to cancer progression in specific niches such as the peritoneal cavity. Our work in this project has identified cancers of the peritoneal cavity cause the upregulated expression of Immunoresponsive Gene-1 (Irg1) in resident macrophages and accumulation of itaconic acid. We found Irg-1 to promote tumors in part through an enhancement of lipid utilization. We found that myeloid cells from the ascites of advanced cancer patients expressed Irg1 and identify Irg-1 as an attractive therapeutic target, since abrogation of Irg-1 expression significantly reduced peritoneal tumor burden in mice. We have extended our work on Irg-1 in the tumor setting with additional dissection of the role of itaconate in macrophage physiology and lipid metabolism. We find that itaconate produced by macrophages in the liver during feeding with high fat diet (HFD), induces an increase in the lipid utilization of hepatocytes, resulting in better control of lipid adiposity. The livers of human non-alcoholic steatohepatitis (NASH) patients show increased expression of Irg-1 and have elevated levels of itaconate. Irg1-/- mice fed HFD have exacerbated liver adiposity and more pronounced metabolic disorder as revealed by worsened glucose and insulin tolerance. Mechanistically, itaconate exposure increases oxidative phosphorylation in hepatocytes by flux analysis, and 13C labeling shows greater amounts of palmitate utilization. We propose that itaconate activated to itaconyl-CoA suppresses substrate-level phosphorylation, reducing ATP levels leading to compensatory increases in lipid utilization. Our ongoing work seeks to extend our study of itaconate physiology and utilize models of tumor-associated macrophage development to define additional regulators of macrophage function in tumors. In addition to direct studies of cancer, we have defined the role of nitric oxide (NO) in the metabolic reprogramming that occurs during macrophage activation. We found that several of the metabolic characteristics of these cells are solely due to the production of NO. The profound effects of NO on the metabolic adaptations of these cells includes control of several key metabolites including itaconate, citrate, alpha-ketoglutarate, and succinate. We had previously found that autologous NO was necessary and sufficient to drive the decline in oxidative phosphorylation associated with "glycolytic commitment". Using unbiased metabolomics, expression analysis, metabolic flux analysis, 13C carbon tracing experiments, and enzymology, we have extensively defined the role of NO in this metabolic reprogramming of macrophages. Our work on this project demonstrates the powerful ability of innate immune cells to not only adapt their metabolic portfolios but to potentially exert metabolic effects in trans by altering the composition of the metabolic niche. Ongoing work more deeply explores the metabolic effects of NO and itaconate in a variety of physiological systems, delves into the tumor-immune crosstalk of the TME, and defines new sources and biology associated with the production of itaconate. Together, these findings define leukocyte metabolic enzymes as bona fide therapeutic targets and demonstrate the importance of understanding immunometabolism in the context of unique physiological niches relevant to cancer.

肿瘤微环境代表了一个复杂的多细胞环境，其中各种细胞类型都竞争其功能所需的资源。肿瘤细胞促进宿主脉管系统的扩张，以维持其快速增殖所需的足够水平。同时，肿瘤细胞征服了宿主防御机制以阻止排斥。已经描述了许多肿瘤介导的免疫抑制的机制，并进行了几种靶向代谢途径。例如，高糖酵解肿瘤在微环境中耗尽葡萄糖，抑制了T细胞增殖和激活。从肿瘤中产生的乳酸升高可以转录重编程肿瘤相关的巨噬细胞进入促进肿瘤生长和进展的免疫抑制细胞。考虑到这些类型的相互作用，我们将肿瘤视为一种独特的代谢环境或利基，其中肿瘤细胞和免疫细胞竞争资源并适应彼此的存在。许多癌症的侵略性反映了肿瘤在这种利基市场中发挥主要作用的能力，从而征服了尝试的免疫反应以促进肿瘤扩张，血管形成和传播。该项目的重点是理解刺激引起的细胞代谢过程改变以及它们在使免疫细胞能够满足与激活相关的代谢需求方面所起的关键作用。因此，我们的工作涉及控制免疫细胞功能的代谢网络的精确解剖，以及对疾病代谢基础的研究。我们在这一领域的工作已经为我们提供了令人兴奋的可能性，可以揭示炎症细胞与肿瘤之间的实质性代谢相互作用。在该项目的一个方面，我们发现在髓样细胞上表达的触发受体（TREM）-1是肾癌中的生物标志物。我们的发现有助于TREM受体家族在包括癌症在内的多种炎症性疾病中起的作用。我们的工作还定义了丙酮酸激酶-2（PKM2）在天然杀伤（NK）细胞和CD4+ T细胞的代谢控制中的规范作用。作为糖酵解的倒数第二个酶，PKM将磷酸烯醇丙酮酸和ADP转化为ATP和丙酮酸，然后将其发酵为乳酸或进口到线粒体中进行氧化。我们的工作已将PKM2确定为NK和T细胞功能的中央代谢调节剂。在NK细胞中，PKM2控制的细胞ROS水平并抑制了MYC信号传导，而在CD4+ T细胞中，PKM2控制丙酮酸氧化，其缺失导致了实质性的氧化细胞死亡。这些发现强调了PKM2作为丙酮酸利用的调节剂的规范功能，并有助于将该代谢途径作为NK和CD4+ T细胞功能的中心调节剂的分配。我们较早的关于腹膜壁基独特性及其在巨噬细胞功能中的作用的工作，其次是我们对癌症中嗜中性粒细胞代谢适应的定义，已经大大地完善了我们对在诸如腹膜腹膜等特定细分市场中有助于癌症进展的代谢适应的理解。我们在该项目中的工作已经确定了腹膜腔的癌症，导致在常驻巨噬细胞中免疫回避基因-1（IRG1）的表达上调，并积累了Itaconic酸。我们发现IRG-1通过增强脂质利用来部分促进肿瘤。我们发现，来自晚期癌症患者腹水的髓样细胞表达IRG1并将IRG-1识别为有吸引力的治疗靶标，因为IRG-1表达的废除显着减少了小鼠的腹膜肿瘤负担。我们已经在肿瘤环境中扩展了IRG-1的工作，并在巨噬细胞生理和脂质代谢中的作用进行了其他解剖。我们发现，高脂肪饮食（HFD）在肝脏中巨噬细胞产生的Itaconate诱导肝细胞的脂质利用率增加，从而更好地控制脂质肥胖。人类非酒精性脂肪性肝炎（NASH）患者的肝脏显示IRG-1的表达增加，并具有升高的Itaconate酸盐。 IRG1 - / - 小鼠喂养的HFD具有恶化的葡萄糖和胰岛素耐受性揭示的肝肥胖和更明显的代谢障碍。从机械上讲，Itaconate暴露通过通量分析增加肝细胞中的氧化磷酸化，而13C标记显示出更多的棕榈酸酯利用率。我们提出，Itaconate激活至itaconyl-COA会抑制底物级磷酸化，从而降低了ATP水平，从而导致脂质利用率增加。我们正在进行的工作旨在扩展我们对Itaconate生理学的研究，并利用与肿瘤相关的巨噬细胞发展模型来定义肿瘤中巨噬细胞功能的其他调节剂。除了直接研究癌症外，我们还定义了一氧化氮（NO）在巨噬细胞激活期间发生的代谢重编程中的作用。我们发现，这些细胞的几种代谢特征仅是由于NO的产生。 NO对这些细胞代谢适应的深远影响包括控制几种关键代谢产物，包括伊龙酸盐，柠檬酸盐，α-酮戊二酸酯和琥珀酸酯。我们以前已经发现，自体NO是必要的，足以驱动与“糖酵解承诺”相关的氧化磷酸化下降。使用无偏的代谢组学，表达分析，代谢通量分析，13C碳追踪实验和酶学，我们已广泛定义了NO在巨噬细胞的代谢重编码中的作用。我们在该项目上的工作展示了先天免疫细胞不仅适应其代谢组合的能力，而且通过改变代谢生态裂的组成而有可能在反式中发挥代谢作用。正在进行的工作更深入地探讨了在多种生理系统中NO和Itaconate的代谢作用，并深入研究了TME的肿瘤免疫串扰，并定义了与Itaconate产生相关的新来源和生物学。这些发现共同将白细胞代谢酶定义为真正的治疗靶标，并证明了在与癌症相关的独特生理壁ches的背景下理解免疫代谢的重要性。

项目成果

Phenotypic heterogeneity in the Gray platelet syndrome extends to the expression of TREM family member, TLT-1.

• DOI: 10.1160/th08-02-0067
• 发表时间: 2008-07
• 期刊: Thrombosis and haemostasis
• 影响因子: 6.7
• 作者: Nurden AT;Nurden P;Bermejo E;Combrié R;McVicar DW;Washington AV
• 通讯作者: Washington AV

Peritoneal tissue-resident macrophages are metabolically poised to engage microbes using tissue-niche fuels.

• DOI: 10.1038/s41467-017-02092-0
• 发表时间: 2017-12-12
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Davies LC;Rice CM;Palmieri EM;Taylor PR;Kuhns DB;McVicar DW
• 通讯作者: McVicar DW

Implications for gene therapy-limiting expression of IL-2R gamma c delineate differences in signaling thresholds required for lymphocyte development and maintenance.

• DOI: 10.4049/jimmunol.0903528
• 发表时间: 2010-08-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Orr SJ;Roessler S;Quigley L;Chan T;Ford JW;O'Connor GM;McVicar DW
• 通讯作者: McVicar DW

Environmental factors determine DAP12 deficiency to either enhance or suppress immunopathogenic processes.

环境因素决定了 DAP12 缺乏会增强或抑制免疫致病过程。

• DOI: 10.1111/imm.12158
• 发表时间: 2013
• 期刊: Immunology
• 影响因子: 6.4
• 作者: Montalvo V;Quigley L;Vistica BP;Boelte KC;Nugent LF;Takai T;McVicar DW;Gery I.
• 通讯作者: Gery I.

Interferon-gamma is Quintessential for NOS2 and COX2 Expression in ER - Breast Tumors that Lead to Poor Outcome.

干扰素-γ 是 ER（导致不良结果的乳腺肿瘤）中 NOS2 和 COX2 表达的典型要素。

• DOI: 10.1101/2023.04.06.535916
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Cheng,RobertYs;Ridnour,LisaA;Wink,AdelaideL;Gonzalez,AnaL;Femino,EliseL;Rittscher,Helene;Somasundarum,Veena;Heinz,WilliamF;Coutinho,Leandro;CristinaRangel,M;Edmondson,ElijahF;Butcher,Donna;Kinders,RobertJ;Li,Xiaoxian;W
• 通讯作者: W