Adenosine in Tumor-Host Interaction

描述（由申请人提供）：代谢应激条件，包括实体瘤的炎症和缺氧特征，哮喘和其他病理条件，导致细胞外腺苷浓度急剧增加。免疫细胞的分化和功能严重依赖于微环境，在一定条件下，肿瘤浸润性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造福肿瘤。我们有初步的数据表明，刺激腺苷受体会使树突状细胞（DC）从正常的免疫保护表型向具有促血管生成和促进肿瘤生长特性的免疫抑制性DC分化。我们还发现腺苷是诱导肿瘤免疫浸润分泌血管内皮生长因子（VEGF）等血管生成因子的重要代谢物，并确定A2B受体是观察到的效应的中介。通过A2B受体的信号传导对肿瘤浸润性免疫细胞分化、细胞因子分泌和肿瘤血管生成的深远影响，确定A2B腺苷受体为重要的治疗靶点。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的细胞因子产生，从而塑造肿瘤微环境。因此，我们也提出了允许区分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。我们假设腺苷信号通过宿主肿瘤浸润免疫细胞上的A2B受体促进肿瘤生长，而治疗性阻断A2B和A2受体信号将改善临床结果并促进抗肿瘤免疫。利用转基因小鼠和骨髓嵌合小鼠，我们打算：1)确定A2B和A2A/A2B受体在癌症中的功能意义；2)确定造血细胞A2受体介导的VEGF生成是否有利于肿瘤生长和血管生成；3)确定靶向A2B和A2受体信号通路的治疗对肿瘤生长和空化、肿瘤浸润免疫细胞和免疫应答的影响。预期的数据将为未来腺苷受体拮抗剂的临床试验奠定基础，并将对癌症和免疫疗法的新治疗方式的发展产生影响。

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.