P2X7 receptor activation impairs antitumour activity of natural killer cells

Background and purpose 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. Experimental approach 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. Key results 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-gamma 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. Conclusions and implications 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.

Automated summary

This study found that activation of the purinergic receptor P2X7 by extracellular ATP impairs the antitumor activity of NK cells, leading to an anergic state and reduced IFN-gamma secretion. This effect can be reversed by specific P2X7 antagonists and pretreatment with IL-2 or IL-15. Knockdown of the P2rx7 gene improved the control of tumor size by NK cells. These findings suggest that P2X7 activation plays a role in NK cell-mediated antitumor effectiveness, and modifying NK cells to lack P2X7 may enhance their antitumor capacity.