TGFβ drives NK cell metabolic dysfunction in human metastatic breast cancer

Background Natural killer (NK) cells provide important immune protection from cancer and are a key requirement for particular immunotherapies. There is accumulating evidence that NK cells become dysfunctional during cancer. Overcoming NK cell exhaustion would be an important step to allow them to fu...

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Autores principales:	Michael Conroy, John Kennedy, Karen Slattery, Elena Woods, Vanessa Zaiatz-Bittencourt, Sam Marks, Sonya Chew, Caitriona Goggin, Colm MacEochagain, Sophie Lucas, David K Finlay, Clair M Gardiner
Formato:	article
Lenguaje:	EN
Publicado:	BMJ Publishing Group 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/b8a8d841ff7e409c8d04b1a423e2c8fe
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spelling	oai:doaj.org-article:b8a8d841ff7e409c8d04b1a423e2c8fe2021-11-16T08:30:04ZTGFβ drives NK cell metabolic dysfunction in human metastatic breast cancer10.1136/jitc-2020-0020442051-1426https://doaj.org/article/b8a8d841ff7e409c8d04b1a423e2c8fe2021-02-01T00:00:00Zhttps://jitc.bmj.com/content/9/2/e002044.fullhttps://doaj.org/toc/2051-1426Background Natural killer (NK) cells provide important immune protection from cancer and are a key requirement for particular immunotherapies. There is accumulating evidence that NK cells become dysfunctional during cancer. Overcoming NK cell exhaustion would be an important step to allow them to function optimally in a range of NK cell therapies, including those that depend on autologos circulating NK cells. We have previously demonstrated that NK cells undergo a normal metabolic reprogramming in response to cytokine activation and that this is required for optimal function. The objective of this work was to investigate if cellular metabolism of circulating NK cells is dysregulated in patients with metastatic breast cancer and if so, to gain insights into potential mechanisms underpinning this. Such discoveries would provide important insights into how to unleash the full activity of NK cells for maximum immunotherapy output.Methods Single-cell analysis, metabolic flux and confocal analysis of NK cells from patients with metastatic breast cancer and healthy controlsResults In addition to reduced interferon-γ production and cytotoxicity, peripheral blood NK cells from patients had clear metabolic deficits including reduced glycolysis and oxidative phosphorylation. There were also distinct morphologically alterations in the mitochondria with increased mitochondrial fragmentation observed. Transforminggrowth factor-β (TGFβ) was identified as a key driver of this phenotype as blocking its activity reversed many metabolic and functional readouts. Expression of glycoprotein-A repetitions predominant (GARP) and latency associated peptide (LAP), which are involved with a novel TGFβ processing pathway, was increased on NK cells from some patients. Blocking the GARP–TGFβ axis recapitulated the effects of TGFβ neutralization, highlighting GARP as a novel NK cell immunotherapy target for the first time.Conclusions TGFβ contributes to metabolic dysfunction of circulating NK cells in patients with metastatic breast cancer. Blocking TGFβ and/or GARP can restore NK cell metabolism and function and is an important target for improving NK cell-based immunotherapies.Michael ConroyJohn KennedyKaren SlatteryElena WoodsVanessa Zaiatz-BittencourtSam MarksSonya ChewCaitriona GogginColm MacEochagainSophie LucasDavid K FinlayClair M GardinerBMJ Publishing GrouparticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENJournal for ImmunoTherapy of Cancer, Vol 9, Iss 2 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Michael Conroy John Kennedy Karen Slattery Elena Woods Vanessa Zaiatz-Bittencourt Sam Marks Sonya Chew Caitriona Goggin Colm MacEochagain Sophie Lucas David K Finlay Clair M Gardiner TGFβ drives NK cell metabolic dysfunction in human metastatic breast cancer
description	Background Natural killer (NK) cells provide important immune protection from cancer and are a key requirement for particular immunotherapies. There is accumulating evidence that NK cells become dysfunctional during cancer. Overcoming NK cell exhaustion would be an important step to allow them to function optimally in a range of NK cell therapies, including those that depend on autologos circulating NK cells. We have previously demonstrated that NK cells undergo a normal metabolic reprogramming in response to cytokine activation and that this is required for optimal function. The objective of this work was to investigate if cellular metabolism of circulating NK cells is dysregulated in patients with metastatic breast cancer and if so, to gain insights into potential mechanisms underpinning this. Such discoveries would provide important insights into how to unleash the full activity of NK cells for maximum immunotherapy output.Methods Single-cell analysis, metabolic flux and confocal analysis of NK cells from patients with metastatic breast cancer and healthy controlsResults In addition to reduced interferon-γ production and cytotoxicity, peripheral blood NK cells from patients had clear metabolic deficits including reduced glycolysis and oxidative phosphorylation. There were also distinct morphologically alterations in the mitochondria with increased mitochondrial fragmentation observed. Transforminggrowth factor-β (TGFβ) was identified as a key driver of this phenotype as blocking its activity reversed many metabolic and functional readouts. Expression of glycoprotein-A repetitions predominant (GARP) and latency associated peptide (LAP), which are involved with a novel TGFβ processing pathway, was increased on NK cells from some patients. Blocking the GARP–TGFβ axis recapitulated the effects of TGFβ neutralization, highlighting GARP as a novel NK cell immunotherapy target for the first time.Conclusions TGFβ contributes to metabolic dysfunction of circulating NK cells in patients with metastatic breast cancer. Blocking TGFβ and/or GARP can restore NK cell metabolism and function and is an important target for improving NK cell-based immunotherapies.
format	article
author	Michael Conroy John Kennedy Karen Slattery Elena Woods Vanessa Zaiatz-Bittencourt Sam Marks Sonya Chew Caitriona Goggin Colm MacEochagain Sophie Lucas David K Finlay Clair M Gardiner
author_facet	Michael Conroy John Kennedy Karen Slattery Elena Woods Vanessa Zaiatz-Bittencourt Sam Marks Sonya Chew Caitriona Goggin Colm MacEochagain Sophie Lucas David K Finlay Clair M Gardiner
author_sort	Michael Conroy
title	TGFβ drives NK cell metabolic dysfunction in human metastatic breast cancer
title_short	TGFβ drives NK cell metabolic dysfunction in human metastatic breast cancer
title_full	TGFβ drives NK cell metabolic dysfunction in human metastatic breast cancer
title_fullStr	TGFβ drives NK cell metabolic dysfunction in human metastatic breast cancer
title_full_unstemmed	TGFβ drives NK cell metabolic dysfunction in human metastatic breast cancer
title_sort	tgfβ drives nk cell metabolic dysfunction in human metastatic breast cancer
publisher	BMJ Publishing Group
publishDate	2021
url	https://doaj.org/article/b8a8d841ff7e409c8d04b1a423e2c8fe
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TGFβ drives NK cell metabolic dysfunction in human metastatic breast cancer

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