Adenosine in Tumor-Host Interaction

腺苷在肿瘤-宿主相互作用中的作用

基本信息

批准号：
8403706
负责人：
MIKHAIL M DIKOV
金额：
$ 33.2万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-07 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8403706
关键词：
Address Adenine Nucleotides Adenosine Adenosine A2 Receptors Adenosine A2A Receptor Adenosine A2B Receptor Adjuvant Affinity Angiogenic Factor Animals Asthma Attenuated Blood Vessels Bone Marrow Cancer Vaccines Cell Differentiation process Cells Characteristics Clinical Clinical Trials Data Dendritic Cells Development Exhibits Foundations Future Hematopoietic Hypoxia Immune Immune Tolerance Immune response Immunity Immunosuppression Immunotherapy In Vitro Inflammation Isogenic transplantation Knockout Mice Malignant Neoplasms Mediating Mediator of activation protein Modality Modeling Mus Myeloid Cells Neoplasm Metastasis Outcome Phenotype Production Property Purinergic P1 Receptors Receptor Signaling Refractory Regulation Resistance Role Shapes Signal Transduction Solid Neoplasm Testing Therapeutic Time Treatment Efficacy Tumor Angiogenesis Tumor Immunity Vascular Endothelial Growth Factors Vascularization angiogenesis cancer immunotherapy cytokine density design extracellular host neoplasm interaction improved in vivo mouse model novel therapeutics public health relevance receptor receptor-mediated signaling research study therapeutic target tumor tumor growth tumor microenvironment

项目摘要

DESCRIPTION (provided by applicant): Metabolically stressful conditions, including inflammation and hypoxia characteristic of solid tumors, asthma and other pathological conditions, result in dramatic increases in extracellular concentrations of adenosine. Differentiation and functionality of immune cells critically depend on the microenvironment and under certain conditions tumor-infiltrating immune cells can benefit tumor by producing factors promoting angiogenesis and suppressing immunity. We have preliminary data demonstrating that stimulation of adenosine receptors skews dendritic cell (DC) differentiation from normal immune protective phenotype toward immune suppressive DC with pro-angiogenic and tumor-growth promoting properties. We also identified adenosine as an important metabolite inducing secretion of angiogenic factors including vascular endothelial growth factor (VEGF) by tumor immune infiltrate and identified A2B receptor as a mediator of the observed effects. The profound effect that signaling through A2B receptor has on differentiation and cytokine secretion by tumor infiltrating immune cells and tumor angiogenesis, identify A2B adenosine receptor as an important therapeutic target. Adenosine shapes tumor microenvironment through regulation the cytokine production by hematopoietic cells via both A2 (A2A and A2B) adenosine receptor-mediated signaling. Thus, we also propose the studies allowing to discriminate between the roles of A2A and A2B receptors in regulation the functions of tumor-infiltrating immune cells. We hypothesize that adenosine signaling through A2B receptor on host tumor-infiltrating immune cells benefits tumor growth and that therapeutic blockage of A2B and A2 receptor signaling will produce improved clinical outcome and benefit anti-tumor immunity. Using genetically modified and bone marrow chimeric mice, we intend to: 1) Determine the functional significance of A2B and A2A/A2B receptor in cancer; 2) Determine whether A2 receptor-mediated VEGF production by hematopoietic cells benefits tumor growth and angiogenesis; 3) Determine the efficacy of therapy targeting A2B and A2 receptor signaling on tumor growth and vacularization, tumor-infiltrating immune cells, and immune responses. The anticipated data will lay the foundation for the future clinical trials of adenosine receptor antagonists and would have implications for the development of novel therapeutic modalities for cancer and immunotherapies.

描述（由申请人提供）：代谢应激状况，包括实体瘤、哮喘和其他病理状况的炎症和缺氧特征，导致细胞外腺苷浓度急剧增加。免疫细胞的分化和功能很大程度上取决于微环境，在某些条件下，肿瘤浸润的免疫细胞可以通过产生促进血管生成和抑制免疫的因子来有益于肿瘤。我们的初步数据表明，刺激腺苷受体会导致树突状细胞 (DC) 从正常免疫保护表型分化为具有促血管生成和肿瘤生长促进特性的免疫抑制性 DC。我们还确定腺苷是通过肿瘤免疫浸润诱导血管生成因子（包括血管内皮生长因子（VEGF））分泌的重要代谢物，并确定 A2B 受体是观察到的效应的介质。通过 A2B 受体的信号传导对肿瘤浸润免疫细胞的分化和细胞因子分泌以及肿瘤血管生成具有深远的影响，因此将 A2B 腺苷受体确定为重要的治疗靶点。腺苷通过 A2（A2A 和 A2B）腺苷受体介导的信号传导调节造血细胞产生细胞因子，从而塑造肿瘤微环境。因此，我们还提出了能够区分 A2A 和 A2B 受体在调节肿瘤浸润免疫细胞功能中的作用的研究。我们假设，通过宿主肿瘤浸润免疫细胞上的 A2B 受体的腺苷信号传导有利于肿瘤生长，并且治疗性阻断 A2B 和 A2 受体信号传导将改善临床结果并有益于抗肿瘤免疫。使用转基因和骨髓嵌合小鼠，我们打算：1）确定A2B和A2A/A2B受体在癌症中的功能意义； 2) 确定A2受体介导的造血细胞产生VEGF是否有利于肿瘤生长和血管生成； 3) 确定针对 A2B 和 A2 受体信号传导的治疗对肿瘤生长和空泡化、肿瘤浸润免疫细胞和免疫反应的功效。预期数据将为腺苷受体拮抗剂的未来临床试验奠定基础，并将对癌症和免疫疗法新型治疗方式的开发产生影响。