Phosphodiesterase 4A confers resistance to PGE2-mediated suppression in CD25+/CD54+ NK cells
Inadequate persistence of tumor-infiltrating natural killer (NK) cells is associated with poor prognosis in cancer patients. The solid tumor microenvironment is characterized by the presence of immunosuppressive factors, including prostaglandin E2 (PGE2), that limit NK cell persistence. Here, we inv...
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| Veröffentlicht in: | EMBO reports 2021-03, Vol.22 (3), p.e51329-n/a |
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| creator | Chen, Ziqing Yang, Ying Neo, Shi Y Shi, Hao Chen, Yi Wagner, Arnika K Larsson, Karin Tong, Le Jakobsson, Per-Johan Alici, Evren Wu, Jing Cao, Yihai Wang, Kai Liu, Lisa L Mao, Yumeng Sarhan, Dhifaf Lundqvist, Andreas |
| description | Inadequate persistence of tumor-infiltrating natural killer (NK) cells is associated with poor prognosis in cancer patients. The solid tumor microenvironment is characterized by the presence of immunosuppressive factors, including prostaglandin E2 (PGE2), that limit NK cell persistence. Here, we investigate if the modulation of the cytokine environment in lung cancer with IL-2 or IL-15 renders NK cells resistant to suppression by PGE2. Analyzing Cancer Genome Atlas (TCGA) data, we found that high NK cell gene signatures correlate with significantly improved overall survival in patients with high levels of the prostaglandin E synthase (PTGES).
In vitro
, IL-15, in contrast to IL-2, enriches for CD25
+
/CD54
+
NK cells with superior mTOR activity and increased expression of the cAMP hydrolyzing enzyme phosphodiesterase 4A (PDE4A). Consequently, this distinct population of NK cells maintains their function in the presence of PGE2 and shows an increased ability to infiltrate lung adenocarcinoma tumors
in vitro
and
in vivo
. Thus, strategies to enrich CD25
+
/CD54
+
NK cells for adoptive cell therapy should be considered.
SYNOPSIS
IL-15 promotes a subset of NK cells that resist PGE2-mediated suppression by mTOR-dependent upregulation of PDE4A. Selective expansion of CD25
+
CD54
+
NK cells for adoptive cell therapy may be used to target tumors with high PGE2 levels.
IL-15 activates mTOR-dependent upregulation of PDE4A in CD25
+
CD54
+
NK cells to resist suppression by PGE2.
CD25
+
CD54
+
NK cells are superior in forming cell clusters and have higher anti-tumor activity in a zebrafish xenograft model.
CD25
+
CD54
+
NK cells efficiently infiltrate human lung adenocarcinoma spheroids.
High NK cell gene signatures correlate with survival in lung adenocarcinoma patients with high prostaglandin E synthase.
Graphical Abstract
IL-15 promotes a subset of NK cells that resist PGE2-mediated suppression by mTOR-dependent upregulation of PDE4A. Selective expansion of CD25
+
CD54
+
NK cells for adoptive cell therapy may be used to target tumors with high PGE2 levels |
| doi_str_mv | 10.15252/embr.202051329 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_C6C</sourceid><recordid>TN_cdi_swepub_primary_oai_swepub_ki_se_464950</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2495308939</sourcerecordid><originalsourceid>FETCH-LOGICAL-c6389-63881fb2dcba210149884380f4f0cee642e7c988b57928ca687f2a19928ec20d3</originalsourceid><addsrcrecordid>eNqFks1v0zAYxiMEYmNw5oYicUEaWW3Hju0dkEpbBmLAhABxQLJc503n0cbBbpj23_OWdt2GVHGxHfv3PHm_suwpJUdUMMEGsJjGI0YYEbRk-l62T3mli5JKdX9zZox-38sepXRBCBFaqofZXllyRYjk-9mPs_OQuvNQe0hLiDZBzoe5C20DMeURkk9L2zrIlyE_O5mwYgG1t0uo89R3Hb4nH9rct_lozMThYDQW_DD_-D53MJ-nx9mDxs4TPNnsB9nXN5Mvo7fF6aeTd6PhaeGqUukCF0WbKavd1DJKKNdK8VKRhjfEAVScgXR4NxVSM-VspWTDLNX4AY6RujzIirVvuoSun5ou-oWNVyZYbzZXP_EEhldcC4K83sl3MdQ3omsh5UJKrqVG7cud2rH_NjQhzkzfGy6w3BLxV2scWSydg3YZ7fzuH--8tP7czMJvg6lW2GA0eLExiOFXj00yC59W1bUthD4Zhp1kUlMmEH3-D3oR-thi5ZHSoiRKl6sEBmvKxZBShGYbDCXm71CZ1VCZ7VCh4tntHLb89RQhcLwGLv0crv7nZyYfXn--7U42BUVdO4N4E_WugP4AWXzorA</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2495308939</pqid></control><display><type>article</type><title>Phosphodiesterase 4A confers resistance to PGE2-mediated suppression in CD25+/CD54+ NK cells</title><source>Springer Nature OA Free Journals</source><creator>Chen, Ziqing ; Yang, Ying ; Neo, Shi Y ; Shi, Hao ; Chen, Yi ; Wagner, Arnika K ; Larsson, Karin ; Tong, Le ; Jakobsson, Per-Johan ; Alici, Evren ; Wu, Jing ; Cao, Yihai ; Wang, Kai ; Liu, Lisa L ; Mao, Yumeng ; Sarhan, Dhifaf ; Lundqvist, Andreas</creator><creatorcontrib>Chen, Ziqing ; Yang, Ying ; Neo, Shi Y ; Shi, Hao ; Chen, Yi ; Wagner, Arnika K ; Larsson, Karin ; Tong, Le ; Jakobsson, Per-Johan ; Alici, Evren ; Wu, Jing ; Cao, Yihai ; Wang, Kai ; Liu, Lisa L ; Mao, Yumeng ; Sarhan, Dhifaf ; Lundqvist, Andreas</creatorcontrib><description>Inadequate persistence of tumor-infiltrating natural killer (NK) cells is associated with poor prognosis in cancer patients. The solid tumor microenvironment is characterized by the presence of immunosuppressive factors, including prostaglandin E2 (PGE2), that limit NK cell persistence. Here, we investigate if the modulation of the cytokine environment in lung cancer with IL-2 or IL-15 renders NK cells resistant to suppression by PGE2. Analyzing Cancer Genome Atlas (TCGA) data, we found that high NK cell gene signatures correlate with significantly improved overall survival in patients with high levels of the prostaglandin E synthase (PTGES).
In vitro
, IL-15, in contrast to IL-2, enriches for CD25
+
/CD54
+
NK cells with superior mTOR activity and increased expression of the cAMP hydrolyzing enzyme phosphodiesterase 4A (PDE4A). Consequently, this distinct population of NK cells maintains their function in the presence of PGE2 and shows an increased ability to infiltrate lung adenocarcinoma tumors
in vitro
and
in vivo
. Thus, strategies to enrich CD25
+
/CD54
+
NK cells for adoptive cell therapy should be considered.
SYNOPSIS
IL-15 promotes a subset of NK cells that resist PGE2-mediated suppression by mTOR-dependent upregulation of PDE4A. Selective expansion of CD25
+
CD54
+
NK cells for adoptive cell therapy may be used to target tumors with high PGE2 levels.
IL-15 activates mTOR-dependent upregulation of PDE4A in CD25
+
CD54
+
NK cells to resist suppression by PGE2.
CD25
+
CD54
+
NK cells are superior in forming cell clusters and have higher anti-tumor activity in a zebrafish xenograft model.
CD25
+
CD54
+
NK cells efficiently infiltrate human lung adenocarcinoma spheroids.
High NK cell gene signatures correlate with survival in lung adenocarcinoma patients with high prostaglandin E synthase.
Graphical Abstract
IL-15 promotes a subset of NK cells that resist PGE2-mediated suppression by mTOR-dependent upregulation of PDE4A. Selective expansion of CD25
+
CD54
+
NK cells for adoptive cell therapy may be used to target tumors with high PGE2 levels</description><identifier>ISSN: 1469-221X</identifier><identifier>ISSN: 1469-3178</identifier><identifier>EISSN: 1469-3178</identifier><identifier>DOI: 10.15252/embr.202051329</identifier><identifier>PMID: 33480074</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Adenocarcinoma ; Cancer ; CD25 antigen ; Cell therapy ; Cytokines ; EMBO03 ; EMBO19 ; EMBO37 ; Genomes ; Lung cancer ; Medical prognosis ; Medicin och hälsovetenskap ; Natural killer cells ; Phosphodiesterase ; Prostaglandin E ; Prostaglandin E2 ; Signatures ; Solid tumors ; Spheroids ; Survival ; TOR protein ; Tumor microenvironment ; Tumors ; Xenografts ; Xenotransplantation ; Zebrafish</subject><ispartof>EMBO reports, 2021-03, Vol.22 (3), p.e51329-n/a</ispartof><rights>The Author(s) 2021</rights><rights>2021 The Authors. Published under the terms of the CC BY 4.0 license</rights><rights>2021 The Authors. Published under the terms of the CC BY 4.0 license.</rights><rights>2021. This article is published under http://creativecommons.org/licenses/by-nc/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c6389-63881fb2dcba210149884380f4f0cee642e7c988b57928ca687f2a19928ec20d3</citedby><cites>FETCH-LOGICAL-c6389-63881fb2dcba210149884380f4f0cee642e7c988b57928ca687f2a19928ec20d3</cites><orcidid>0000-0001-5077-2250 ; 0000-0003-0839-6516 ; 0000-0002-9709-2970</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926252/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926252/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,552,727,780,784,885,1417,1433,27924,27925,41120,42189,45574,45575,46409,46833,51576,53791,53793</link.rule.ids><linktorsrc>$$Uhttps://doi.org/10.15252/embr.202051329$$EView_record_in_Springer_Nature$$FView_record_in_$$GSpringer_Nature</linktorsrc><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33480074$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-450007$$DView record from Swedish Publication Index$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:145774979$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Chen, Ziqing</creatorcontrib><creatorcontrib>Yang, Ying</creatorcontrib><creatorcontrib>Neo, Shi Y</creatorcontrib><creatorcontrib>Shi, Hao</creatorcontrib><creatorcontrib>Chen, Yi</creatorcontrib><creatorcontrib>Wagner, Arnika K</creatorcontrib><creatorcontrib>Larsson, Karin</creatorcontrib><creatorcontrib>Tong, Le</creatorcontrib><creatorcontrib>Jakobsson, Per-Johan</creatorcontrib><creatorcontrib>Alici, Evren</creatorcontrib><creatorcontrib>Wu, Jing</creatorcontrib><creatorcontrib>Cao, Yihai</creatorcontrib><creatorcontrib>Wang, Kai</creatorcontrib><creatorcontrib>Liu, Lisa L</creatorcontrib><creatorcontrib>Mao, Yumeng</creatorcontrib><creatorcontrib>Sarhan, Dhifaf</creatorcontrib><creatorcontrib>Lundqvist, Andreas</creatorcontrib><title>Phosphodiesterase 4A confers resistance to PGE2-mediated suppression in CD25+/CD54+ NK cells</title><title>EMBO reports</title><addtitle>EMBO Rep</addtitle><addtitle>EMBO Rep</addtitle><description>Inadequate persistence of tumor-infiltrating natural killer (NK) cells is associated with poor prognosis in cancer patients. The solid tumor microenvironment is characterized by the presence of immunosuppressive factors, including prostaglandin E2 (PGE2), that limit NK cell persistence. Here, we investigate if the modulation of the cytokine environment in lung cancer with IL-2 or IL-15 renders NK cells resistant to suppression by PGE2. Analyzing Cancer Genome Atlas (TCGA) data, we found that high NK cell gene signatures correlate with significantly improved overall survival in patients with high levels of the prostaglandin E synthase (PTGES).
In vitro
, IL-15, in contrast to IL-2, enriches for CD25
+
/CD54
+
NK cells with superior mTOR activity and increased expression of the cAMP hydrolyzing enzyme phosphodiesterase 4A (PDE4A). Consequently, this distinct population of NK cells maintains their function in the presence of PGE2 and shows an increased ability to infiltrate lung adenocarcinoma tumors
in vitro
and
in vivo
. Thus, strategies to enrich CD25
+
/CD54
+
NK cells for adoptive cell therapy should be considered.
SYNOPSIS
IL-15 promotes a subset of NK cells that resist PGE2-mediated suppression by mTOR-dependent upregulation of PDE4A. Selective expansion of CD25
+
CD54
+
NK cells for adoptive cell therapy may be used to target tumors with high PGE2 levels.
IL-15 activates mTOR-dependent upregulation of PDE4A in CD25
+
CD54
+
NK cells to resist suppression by PGE2.
CD25
+
CD54
+
NK cells are superior in forming cell clusters and have higher anti-tumor activity in a zebrafish xenograft model.
CD25
+
CD54
+
NK cells efficiently infiltrate human lung adenocarcinoma spheroids.
High NK cell gene signatures correlate with survival in lung adenocarcinoma patients with high prostaglandin E synthase.
Graphical Abstract
IL-15 promotes a subset of NK cells that resist PGE2-mediated suppression by mTOR-dependent upregulation of PDE4A. Selective expansion of CD25
+
CD54
+
NK cells for adoptive cell therapy may be used to target tumors with high PGE2 levels</description><subject>Adenocarcinoma</subject><subject>Cancer</subject><subject>CD25 antigen</subject><subject>Cell therapy</subject><subject>Cytokines</subject><subject>EMBO03</subject><subject>EMBO19</subject><subject>EMBO37</subject><subject>Genomes</subject><subject>Lung cancer</subject><subject>Medical prognosis</subject><subject>Medicin och hälsovetenskap</subject><subject>Natural killer cells</subject><subject>Phosphodiesterase</subject><subject>Prostaglandin E</subject><subject>Prostaglandin E2</subject><subject>Signatures</subject><subject>Solid tumors</subject><subject>Spheroids</subject><subject>Survival</subject><subject>TOR protein</subject><subject>Tumor microenvironment</subject><subject>Tumors</subject><subject>Xenografts</subject><subject>Xenotransplantation</subject><subject>Zebrafish</subject><issn>1469-221X</issn><issn>1469-3178</issn><issn>1469-3178</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>D8T</sourceid><recordid>eNqFks1v0zAYxiMEYmNw5oYicUEaWW3Hju0dkEpbBmLAhABxQLJc503n0cbBbpj23_OWdt2GVHGxHfv3PHm_suwpJUdUMMEGsJjGI0YYEbRk-l62T3mli5JKdX9zZox-38sepXRBCBFaqofZXllyRYjk-9mPs_OQuvNQe0hLiDZBzoe5C20DMeURkk9L2zrIlyE_O5mwYgG1t0uo89R3Hb4nH9rct_lozMThYDQW_DD_-D53MJ-nx9mDxs4TPNnsB9nXN5Mvo7fF6aeTd6PhaeGqUukCF0WbKavd1DJKKNdK8VKRhjfEAVScgXR4NxVSM-VspWTDLNX4AY6RujzIirVvuoSun5ou-oWNVyZYbzZXP_EEhldcC4K83sl3MdQ3omsh5UJKrqVG7cud2rH_NjQhzkzfGy6w3BLxV2scWSydg3YZ7fzuH--8tP7czMJvg6lW2GA0eLExiOFXj00yC59W1bUthD4Zhp1kUlMmEH3-D3oR-thi5ZHSoiRKl6sEBmvKxZBShGYbDCXm71CZ1VCZ7VCh4tntHLb89RQhcLwGLv0crv7nZyYfXn--7U42BUVdO4N4E_WugP4AWXzorA</recordid><startdate>20210303</startdate><enddate>20210303</enddate><creator>Chen, Ziqing</creator><creator>Yang, Ying</creator><creator>Neo, Shi Y</creator><creator>Shi, Hao</creator><creator>Chen, Yi</creator><creator>Wagner, Arnika K</creator><creator>Larsson, Karin</creator><creator>Tong, Le</creator><creator>Jakobsson, Per-Johan</creator><creator>Alici, Evren</creator><creator>Wu, Jing</creator><creator>Cao, Yihai</creator><creator>Wang, Kai</creator><creator>Liu, Lisa L</creator><creator>Mao, Yumeng</creator><creator>Sarhan, Dhifaf</creator><creator>Lundqvist, Andreas</creator><general>Nature Publishing Group UK</general><general>Blackwell Publishing Ltd</general><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>WIN</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>7T5</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>ACNBI</scope><scope>ADTPV</scope><scope>AOWAS</scope><scope>D8T</scope><scope>DF2</scope><scope>ZZAVC</scope><orcidid>https://orcid.org/0000-0001-5077-2250</orcidid><orcidid>https://orcid.org/0000-0003-0839-6516</orcidid><orcidid>https://orcid.org/0000-0002-9709-2970</orcidid></search><sort><creationdate>20210303</creationdate><title>Phosphodiesterase 4A confers resistance to PGE2-mediated suppression in CD25+/CD54+ NK cells</title><author>Chen, Ziqing ; Yang, Ying ; Neo, Shi Y ; Shi, Hao ; Chen, Yi ; Wagner, Arnika K ; Larsson, Karin ; Tong, Le ; Jakobsson, Per-Johan ; Alici, Evren ; Wu, Jing ; Cao, Yihai ; Wang, Kai ; Liu, Lisa L ; Mao, Yumeng ; Sarhan, Dhifaf ; Lundqvist, Andreas</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c6389-63881fb2dcba210149884380f4f0cee642e7c988b57928ca687f2a19928ec20d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Adenocarcinoma</topic><topic>Cancer</topic><topic>CD25 antigen</topic><topic>Cell therapy</topic><topic>Cytokines</topic><topic>EMBO03</topic><topic>EMBO19</topic><topic>EMBO37</topic><topic>Genomes</topic><topic>Lung cancer</topic><topic>Medical prognosis</topic><topic>Medicin och hälsovetenskap</topic><topic>Natural killer cells</topic><topic>Phosphodiesterase</topic><topic>Prostaglandin E</topic><topic>Prostaglandin E2</topic><topic>Signatures</topic><topic>Solid tumors</topic><topic>Spheroids</topic><topic>Survival</topic><topic>TOR protein</topic><topic>Tumor microenvironment</topic><topic>Tumors</topic><topic>Xenografts</topic><topic>Xenotransplantation</topic><topic>Zebrafish</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chen, Ziqing</creatorcontrib><creatorcontrib>Yang, Ying</creatorcontrib><creatorcontrib>Neo, Shi Y</creatorcontrib><creatorcontrib>Shi, Hao</creatorcontrib><creatorcontrib>Chen, Yi</creatorcontrib><creatorcontrib>Wagner, Arnika K</creatorcontrib><creatorcontrib>Larsson, Karin</creatorcontrib><creatorcontrib>Tong, Le</creatorcontrib><creatorcontrib>Jakobsson, Per-Johan</creatorcontrib><creatorcontrib>Alici, Evren</creatorcontrib><creatorcontrib>Wu, Jing</creatorcontrib><creatorcontrib>Cao, Yihai</creatorcontrib><creatorcontrib>Wang, Kai</creatorcontrib><creatorcontrib>Liu, Lisa L</creatorcontrib><creatorcontrib>Mao, Yumeng</creatorcontrib><creatorcontrib>Sarhan, Dhifaf</creatorcontrib><creatorcontrib>Lundqvist, Andreas</creatorcontrib><collection>Wiley Online Library (Open Access Collection)</collection><collection>Wiley Free Content</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>SWEPUB Uppsala universitet full text</collection><collection>SwePub</collection><collection>SwePub Articles</collection><collection>SWEPUB Freely available online</collection><collection>SWEPUB Uppsala universitet</collection><collection>SwePub Articles full text</collection><jtitle>EMBO reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext_linktorsrc</fulltext></delivery><addata><au>Chen, Ziqing</au><au>Yang, Ying</au><au>Neo, Shi Y</au><au>Shi, Hao</au><au>Chen, Yi</au><au>Wagner, Arnika K</au><au>Larsson, Karin</au><au>Tong, Le</au><au>Jakobsson, Per-Johan</au><au>Alici, Evren</au><au>Wu, Jing</au><au>Cao, Yihai</au><au>Wang, Kai</au><au>Liu, Lisa L</au><au>Mao, Yumeng</au><au>Sarhan, Dhifaf</au><au>Lundqvist, Andreas</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Phosphodiesterase 4A confers resistance to PGE2-mediated suppression in CD25+/CD54+ NK cells</atitle><jtitle>EMBO reports</jtitle><stitle>EMBO Rep</stitle><addtitle>EMBO Rep</addtitle><date>2021-03-03</date><risdate>2021</risdate><volume>22</volume><issue>3</issue><spage>e51329</spage><epage>n/a</epage><pages>e51329-n/a</pages><issn>1469-221X</issn><issn>1469-3178</issn><eissn>1469-3178</eissn><abstract>Inadequate persistence of tumor-infiltrating natural killer (NK) cells is associated with poor prognosis in cancer patients. The solid tumor microenvironment is characterized by the presence of immunosuppressive factors, including prostaglandin E2 (PGE2), that limit NK cell persistence. Here, we investigate if the modulation of the cytokine environment in lung cancer with IL-2 or IL-15 renders NK cells resistant to suppression by PGE2. Analyzing Cancer Genome Atlas (TCGA) data, we found that high NK cell gene signatures correlate with significantly improved overall survival in patients with high levels of the prostaglandin E synthase (PTGES).
In vitro
, IL-15, in contrast to IL-2, enriches for CD25
+
/CD54
+
NK cells with superior mTOR activity and increased expression of the cAMP hydrolyzing enzyme phosphodiesterase 4A (PDE4A). Consequently, this distinct population of NK cells maintains their function in the presence of PGE2 and shows an increased ability to infiltrate lung adenocarcinoma tumors
in vitro
and
in vivo
. Thus, strategies to enrich CD25
+
/CD54
+
NK cells for adoptive cell therapy should be considered.
SYNOPSIS
IL-15 promotes a subset of NK cells that resist PGE2-mediated suppression by mTOR-dependent upregulation of PDE4A. Selective expansion of CD25
+
CD54
+
NK cells for adoptive cell therapy may be used to target tumors with high PGE2 levels.
IL-15 activates mTOR-dependent upregulation of PDE4A in CD25
+
CD54
+
NK cells to resist suppression by PGE2.
CD25
+
CD54
+
NK cells are superior in forming cell clusters and have higher anti-tumor activity in a zebrafish xenograft model.
CD25
+
CD54
+
NK cells efficiently infiltrate human lung adenocarcinoma spheroids.
High NK cell gene signatures correlate with survival in lung adenocarcinoma patients with high prostaglandin E synthase.
Graphical Abstract
IL-15 promotes a subset of NK cells that resist PGE2-mediated suppression by mTOR-dependent upregulation of PDE4A. Selective expansion of CD25
+
CD54
+
NK cells for adoptive cell therapy may be used to target tumors with high PGE2 levels</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>33480074</pmid><doi>10.15252/embr.202051329</doi><tpages>17</tpages><orcidid>https://orcid.org/0000-0001-5077-2250</orcidid><orcidid>https://orcid.org/0000-0003-0839-6516</orcidid><orcidid>https://orcid.org/0000-0002-9709-2970</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext_linktorsrc |
| identifier | ISSN: 1469-221X |
| ispartof | EMBO reports, 2021-03, Vol.22 (3), p.e51329-n/a |
| issn | 1469-221X 1469-3178 1469-3178 |
| language | eng |
| recordid | cdi_swepub_primary_oai_swepub_ki_se_464950 |
| source | Springer Nature OA Free Journals |
| subjects | Adenocarcinoma Cancer CD25 antigen Cell therapy Cytokines EMBO03 EMBO19 EMBO37 Genomes Lung cancer Medical prognosis Medicin och hälsovetenskap Natural killer cells Phosphodiesterase Prostaglandin E Prostaglandin E2 Signatures Solid tumors Spheroids Survival TOR protein Tumor microenvironment Tumors Xenografts Xenotransplantation Zebrafish |
| title | Phosphodiesterase 4A confers resistance to PGE2-mediated suppression in CD25+/CD54+ NK cells |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-04T09%3A12%3A05IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_C6C&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Phosphodiesterase%204A%20confers%20resistance%20to%20PGE2-mediated%20suppression%20in%20CD25+/CD54+%20NK%20cells&rft.jtitle=EMBO%20reports&rft.au=Chen,%20Ziqing&rft.date=2021-03-03&rft.volume=22&rft.issue=3&rft.spage=e51329&rft.epage=n/a&rft.pages=e51329-n/a&rft.issn=1469-221X&rft.eissn=1469-3178&rft_id=info:doi/10.15252/embr.202051329&rft_dat=%3Cproquest_C6C%3E2495308939%3C/proquest_C6C%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2495308939&rft_id=info:pmid/33480074&rfr_iscdi=true |