P2X7 receptor activation impairs antitumour activity of natural killer cells.
P2X7 receptor activation impairs antitumour activity of natural killer cells.
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DOI：
10.1111/bph.15951
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发表时间：
2023-01
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
--
作者：
大量肿瘤内浸润的自然杀伤 (NK) 细胞与多种癌症的更好生存相关，构成对抗肿瘤的重要第一道防线。实体瘤核心的缺氧会诱导细胞应激和 ATP 释放到细胞外空间，从而触发肿瘤相关免疫细胞上的嘌呤能受体激活。本研究的目的是评估胞外 ATP 激活嘌呤受体 P2X7 是否在 NK 细胞抗肿瘤活性中发挥作用。我们使用细胞外 ATP 通过 P2X7 触发的纯化人 NK 细胞进行了体外实验。通过 NK 细胞毒性测定研究 NK 细胞对肿瘤靶细胞 K562 的杀伤活性。同样，我们设计了皮下实体瘤体内小鼠模型。在这项研究中，我们发现表达功能性质膜 P2X7 的人类 NK 细胞在 ATP 处理后获得无能状态，从而损害其抗肿瘤活性并减少 IFN-γ 分泌。这种效应可以通过特定的 P2X7 拮抗剂和 IL-2 或 IL-15 预处理来逆转。此外，基因 P2rx7 敲除可改善 NK 细胞对肿瘤大小的控制。此外，IL-2 疗法恢复了 NK 细胞缩小肿瘤大小的能力。我们的结果表明，P2X7 激活代表了一种新机制，NK 细胞可能会失去抗肿瘤功效，从而开启了生成缺乏 P2X7 但抗肿瘤能力提高的修饰 NK 细胞的可能性。
A high number of intratumoural infiltrating natural killer (NK) cells is associated with better survival in several types of cancer, constituting an important first line of defence against tumours. Hypoxia in the core of solid tumours induces cellular stress and ATP release into the extracellular space where it triggers purinergic receptor activation on tumour‐associated immune cells. The aim of this study was to assess whether activation of the purinergic receptor P2X7 by extracellular ATP plays a role in the NK cells antitumour activity. We carried out in vitro experiments using purified human NK cells triggered through P2X7 by extracellular ATP. NK cell killing activity against the tumour target cells K562 was studied by means of NK cytotoxicity assays. Likewise, we designed a subcutaneous solid tumour in vivo mouse model. In this study we found that human NK cells, expressing a functional plasma membrane P2X7, acquired an anergic state after ATP treatment, which impaired their antitumour activity and decreased IFN‐γ secretion. This effect was reversed by specific P2X7 antagonists and pretreatment with either IL‐2 or IL‐15. Furthermore, genetic P2rx7 knockdown resulted in improved control of tumour size by NK cells. In addition, IL‐2 therapy restored the ability of NK cells to diminish the size of tumours. Our results show that P2X7 activation represents a new mechanism whereby NK cells may lose antitumour effectiveness, opening the possibility of generating modified NK cells lacking P2X7 but with improved antitumour capacity.
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影响因子：
8
作者：
Gilbert SM;Oliphant CJ;Hassan S;Peille AL;Bronsert P;Falzoni S;Di Virgilio F;McNulty S;Lara R
通讯作者：
Lara R
影响因子：
28.2
作者：
Cózar B;Greppi M;Carpentier S;Narni-Mancinelli E;Chiossone L;Vivier E
通讯作者：
Vivier E
影响因子：
3.4
作者：
Dubyak GR
通讯作者：
Dubyak GR
巨噬细胞激活和极化改变 P2X7 受体分泌组，影响炎症过程。
影响因子：
4.6
作者：
de Torre-Minguela C;Barberà-Cremades M;Gómez AI;Martín-Sánchez F;Pelegrín P
通讯作者：
Pelegrín P
影响因子：
3.5
作者：
Adinolfi, Elena;Pizzirani, Cinzia;Idzko, Marco;Panther, Elisabeth;Norgauer, Johannes;Di Virgilio, Francesco;Ferrari, Davide
通讯作者：
Ferrari, Davide