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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 i...

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Autores principales: Baroja‐Mazo, Alberto, Peñín‐Franch, Alejandro, Lucas‐Ruiz, Fernando, de Torre‐Minguela, Carlos, Alarcón‐Vila, Cristina, Hernández‐Caselles, Trinidad, Pelegrín, Pablo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10092446/
https://www.ncbi.nlm.nih.gov/pubmed/36098250
http://dx.doi.org/10.1111/bph.15951
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author Baroja‐Mazo, Alberto
Peñín‐Franch, Alejandro
Lucas‐Ruiz, Fernando
de Torre‐Minguela, Carlos
Alarcón‐Vila, Cristina
Hernández‐Caselles, Trinidad
Pelegrín, Pablo
author_facet Baroja‐Mazo, Alberto
Peñín‐Franch, Alejandro
Lucas‐Ruiz, Fernando
de Torre‐Minguela, Carlos
Alarcón‐Vila, Cristina
Hernández‐Caselles, Trinidad
Pelegrín, Pablo
author_sort Baroja‐Mazo, Alberto
collection PubMed
description 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‐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. 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.
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spelling pubmed-100924462023-04-13 P2X7 receptor activation impairs antitumour activity of natural killer cells Baroja‐Mazo, Alberto Peñín‐Franch, Alejandro Lucas‐Ruiz, Fernando de Torre‐Minguela, Carlos Alarcón‐Vila, Cristina Hernández‐Caselles, Trinidad Pelegrín, Pablo Br J Pharmacol Research Articles 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‐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. 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. John Wiley and Sons Inc. 2022-10-03 2023-01 /pmc/articles/PMC10092446/ /pubmed/36098250 http://dx.doi.org/10.1111/bph.15951 Text en © 2022 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Research Articles
Baroja‐Mazo, Alberto
Peñín‐Franch, Alejandro
Lucas‐Ruiz, Fernando
de Torre‐Minguela, Carlos
Alarcón‐Vila, Cristina
Hernández‐Caselles, Trinidad
Pelegrín, Pablo
P2X7 receptor activation impairs antitumour activity of natural killer cells
title P2X7 receptor activation impairs antitumour activity of natural killer cells
title_full P2X7 receptor activation impairs antitumour activity of natural killer cells
title_fullStr P2X7 receptor activation impairs antitumour activity of natural killer cells
title_full_unstemmed P2X7 receptor activation impairs antitumour activity of natural killer cells
title_short P2X7 receptor activation impairs antitumour activity of natural killer cells
title_sort p2x7 receptor activation impairs antitumour activity of natural killer cells
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10092446/
https://www.ncbi.nlm.nih.gov/pubmed/36098250
http://dx.doi.org/10.1111/bph.15951
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