Adenosine in Tumor-Host Interaction

描述(由申请人提供)：代谢压力条件，包括实体肿瘤的炎症和缺氧特征，哮喘和其他病理情况，导致细胞外腺苷浓度急剧增加。免疫细胞的分化和功能在很大程度上依赖于微环境，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而使肿瘤受益。我们有初步的数据表明，腺苷受体的刺激使树突状细胞(DC)从正常的免疫保护性表型分化为具有促血管生成和促进肿瘤生长特性的免疫抑制性DC。我们还发现腺苷是一种重要的代谢产物，可以通过肿瘤免疫浸润液诱导包括血管内皮生长因子(VEGF)在内的血管生成因子的分泌，并且A2B受体是观察到的效应的中介。A2B受体信号转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刻影响，使A2B受体成为重要的治疗靶点。腺苷通过A2(A2A和A2B)腺苷受体介导的信号调节造血细胞产生的细胞因子，从而塑造肿瘤微环境。因此，我们还建议进行研究，以区分A2A和A2B受体在调节肿瘤浸润性免疫细胞功能中的作用。我们假设，通过宿主肿瘤浸润性免疫细胞上的A2B受体传递的腺苷信号有利于肿瘤的生长，阻断A2B和A2受体信号传递的治疗将产生改善的临床结果，并有利于抗肿瘤免疫。利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的VEGF是否有利于肿瘤的生长和血管生成；3)确定针对A2B和A2受体信号对肿瘤生长和空化、肿瘤浸润性免疫细胞和免疫反应的治疗效果。这些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开发产生影响。 公共卫生相关性：本研究的目的是确定A2腺苷受体介导的腺苷信号在肿瘤浸润性髓系细胞异常分化和激活、诱导免疫抑制和耐受以及促进肿瘤生长和血管形成中的作用。对A2受体信号通路的阻断能否改善临床疗效，是否有利于抗肿瘤免疫，以及辅助应用A2受体信号通路是否能增强抗血管生成的疗效，这一重要问题将会得到解决。这些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，并将对开发新的癌症治疗方式，特别是抗血管生成和免疫治疗具有重要意义。

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. PUBLIC HEALTH RELEVANCE: The purpose of this study is to determine the role of adenosine signaling mediated via A2 adenosine receptor in aberrant differentiation and activation of tumor infiltrating myeloid cells, induction of immune suppression and tolerance and promoting tumor growth and vascularization. The important question of whether therapeutic blockage of A2 receptor signaling can produce improved clinical outcome and benefit anti-tumor immunity and whether adjuvant application of such therapy can enhance the efficacy of anti-angiogenic will be addressed. 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, anti-angiogenic and immunotherapies in particular.