Cancer Exosomes Express CD39 and CD73, Which Suppress T Cells through Adenosine Production
Cancer Exosomes Express CD39 and CD73, Which Suppress T Cells through Adenosine Production
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DOI：
10.4049/jimmunol.1003884
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发表时间：
2011-07-15
影响因子：
4.4
通讯作者：
Tabi, Zsuzsanna
中科院分区：
文献类型：
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作者：
Clayton, Aled;Al-Taei, Saly;Tabi, Zsuzsanna
细胞外腺苷在癌组织中升高，并且它负调节局部免疫应答。从细胞外ATP产生腺苷作为调节性T细胞介导的免疫调节的机制已引起关注。在这项研究中，我们研究了癌细胞分泌的小泡（称为外泌体）是否有助于细胞外腺苷的产生，从而间接调节免疫效应细胞。我们发现来自不同癌细胞类型的外泌体表现出有效的ATP-和5 'AMP-磷酸水解活性，部分归因于外泌体分别表达的CD 39和CD 73。用来自间皮瘤患者胸腔积液的外来体观察到相当水平的活性。在这样的流体中，外泌体占总ATP水解活性的20%。外泌体可以依次进行两个水解步骤以从ATP形成腺苷。这种外泌体产生的腺苷可以在腺苷A（2A）受体阳性而不是A（2A）受体阴性细胞中触发cAMP反应。类似地，在Jurkat细胞中，通过添加外泌体与ATP也触发了显著升高的cAMP，但单独添加外泌体或ATP则没有。一部分健康供体T细胞组成型表达⑶ 39和/或⑶ 73。通过CD 3/CD 28交联激活T细胞可以被外源性添加的59 AMP以CD 73依赖性方式抑制。然而，59 AMP通过外泌体转化为腺苷抑制T细胞活化，而不依赖于T细胞CD 73表达。这种T细胞抑制是通过腺苷A（2A）受体介导的。总之，这些数据突出了胞外腺苷产生中的外泌体酶活性，这可能在肿瘤环境中T细胞的负调节中起作用。免疫学杂志，2011，187：676-683。
Extracellular adenosine is elevated in cancer tissue, and it negatively regulates local immune responses. Adenosine production from extracellular ATP has attracted attention as a mechanism of regulatory T cell-mediated immune regulation. In this study, we examined whether small vesicles secreted by cancer cells, called exosomes, contribute to extracellular adenosine production and hence modulate immune effector cells indirectly. We found exosomes from diverse cancer cell types exhibit potent ATP- and 5'AMP-phosphohydrolytic activity, partly attributed to exosomally expressed CD39 and CD73, respectively. Comparable levels of activity were seen with exosomes from pleural effusions of mesothelioma patients. In such fluids, exosomes accounted for 20% of the total ATP-hydrolytic activity. Exosomes can perform both hydrolytic steps sequentially to form adenosine from ATP. This exosome-generated adenosine can trigger a cAMP response in adenosine A(2A) receptor-positive but not A(2A) receptor-negative cells. Similarly, significantly elevated cAMP was also triggered in Jurkat cells by adding exosomes with ATP but not by adding exosomes or ATP alone. A proportion of healthy donor T cells constitutively express CD39 and/or CD73. Activation of T cells by CD3/CD28 cross-linking could be inhibited by exogenously added 59AMP in a CD73-dependent manner. However, 59AMP converted to adenosine by exosomes inhibits T cell activation independently of T cell CD73 expression. This T cell inhibition was mediated through the adenosine A(2A) receptor. In summary, the data highlight exosome enzymic activity in the production of extracellular adenosine, and this may play a contributory role in negative modulation of T cells in the tumor environment. The Journal of Immunology, 2011, 187: 676-683.