A CD38/CD203a/CD73 ectoenzymatic pathway independent of CD39 drives a novel adenosinergic loop in human T lymphocytes.
A CD38/CD203a/CD73 ectoenzymatic pathway independent of CD39 drives a novel adenosinergic loop in human T lymphocytes.
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DOI：
10.4161/onci.26246
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发表时间：
2013-09-01
期刊：
影响因子：
7.2
通讯作者：
Malavasi F
中科院分区：
文献类型：
--
作者：
Horenstein AL;Chillemi A;Zaccarello G;Bruzzone S;Quarona V;Zito A;Serra S;Malavasi F
肿瘤微环境的特征是高水平的细胞外核苷酸，这些核苷酸通过细胞表面酶（胞外酶）的动态和连续作用进行代谢。这些胞外酶根据其空间排列发挥作用，作为（1）连续（同一细胞上的分子）或（2）不连续（不同细胞上的分子）途径的一部分，后者受到有限的细胞微环境的促进。这种分解代谢活动的结果是腺苷局部浓度增加，腺苷是一种参与控制炎症和免疫反应的核苷。这里介绍的工作的目的是证明以前未探索的酶途径可能是生产细胞外腺苷的替代途径。我们的数据表明，这个新轴由核苷酸代谢胞外酶 CD38（一种 NAD+ 核苷酶）、胞外核苷酸焦磷酸酶/磷酸二酯酶 1（NPP1，也称为 CD203a 或 PC-1）和 5' 胞外核苷酸酶 (5'-NT) CD73 驱动，同时绕过了由胞外核苷酸介导的典型分解代谢途径。核苷三磷酸水解酶和二磷酸水解酶 (NTPDase) CD39。为了确定这些细胞表面酶对腺苷产生的相对贡献，我们利用了人类 T 细胞模型，允许在激活和转染时模块化表达该替代途径的各个组件。通过高效液相色谱（HPLC）对这些胞外酶产物的生化分析充分证实了我们的工作假设。这种新表征的途径可能有助于在选定的细胞环境中出现适应性免疫反应。考虑到细胞外腺苷在炎症和免疫原性调节中的作用，该途径可能构成一种新的肿瘤逃避策略，这意味着这些酶可能代表抗体介导治疗的理想靶标。
The tumor microenvironment is characterized by of high levels of extracellular nucleotides that are metabolized through the dynamic and sequential action of cell surface enzymes (ectoenzymes). These ectoenzymes operate according to their spatial arrangement, as part of (1) continuous (molecules on the same cell) or (2) discontinuous (molecules on different cells) pathways, the latter being facilitated by restricted cellular microenvironment. The outcome of this catabolic activity is an increase in the local concentration of adenosine, a nucleoside involved in the control of inflammation and immune responses. The aim of the work presented here was to demonstrate that a previously unexplored enzymatic pathway may be an alternate route to produce extracellular adenosine. Our data show that this new axis is driven by the nucleotide-metabolizing ectoenzymes CD38 (an NAD+ nucleosidase), the ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1, also known as CD203a or PC-1) and the 5′ ectonucleotidase (5′-NT) CD73, while bypassing the canonical catabolic pathway mediated by the nucleoside tri- and diphosphohydrolase (NTPDase) CD39. To determine the relative contributions of these cell surface enzymes to the production of adenosine, we exploited a human T-cell model allowing for the modular expression of the individual components of this alternative pathway upon activation and transfection. The biochemical analysis of the products of these ectoenzymes by high-performance liquid chromatography (HPLC) fully substantiated our working hypothesis. This newly characterized pathway may facilitate the emergence of an adaptive immune response in selected cellular contexts. Considering the role for extracellular adenosine in the regulation of inflammation and immunogenicity, this pathway could constitute a novel strategy of tumor evasion, implying that these enzymes may represent ideal targets for antibody-mediated therapy.