Human Tumour Immune Evasion via TGF-[beta] Blocks NK Cell Activation but Not Survival Allowing Therapeutic Restoration of Anti-Tumour Activity
Immune evasion is now recognized as a key feature of cancer progression. In animal models, the activity of cytotoxic lymphocytes is suppressed in the tumour microenvironment by the immunosuppressive cytokine, Transforming Growth Factor (TGF)-[beta]. Release from TGF-[beta]-mediated inhibition restor...
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| Veröffentlicht in: | PloS one 2011-09, Vol.6 (9), p.e22842 |
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| creator | Wilson, Erica B El-Jawhari, Jehan J Neilson, Abbie L Hall, Geoffrey D Melcher, Alan A Meade, Josephine L Cook, Graham P |
| description | Immune evasion is now recognized as a key feature of cancer progression. In animal models, the activity of cytotoxic lymphocytes is suppressed in the tumour microenvironment by the immunosuppressive cytokine, Transforming Growth Factor (TGF)-[beta]. Release from TGF-[beta]-mediated inhibition restores anti-tumour immunity, suggesting a therapeutic strategy for human cancer. We demonstrate that human natural killer (NK) cells are inhibited in a TGF-[beta] dependent manner following chronic contact-dependent interactions with tumour cells in vitro. In vivo, NK cell inhibition was localised to the human tumour microenvironment and primary ovarian tumours conferred TGF-[beta] dependent inhibition upon autologous NK cells ex vivo. TGF-[beta] antagonized the interleukin (IL)-15 induced proliferation and gene expression associated with NK cell activation, inhibiting the expression of both NK cell activation receptor molecules and components of the cytotoxic apparatus. Interleukin-15 also promotes NK cell survival and IL-15 excluded the pro-apoptotic transcription factor FOXO3 from the nucleus. However, this IL-15 mediated pathway was unaffected by TGF-[beta] treatment, allowing NK cell survival. This suggested that NK cells in the tumour microenvironment might have their activity restored by TGF-[beta] blockade and both anti-TGF-[beta] antibodies and a small molecule inhibitor of TGF-[beta] signalling restored the effector function of NK cells inhibited by autologous tumour cells. Thus, TGF-[beta] blunts NK cell activation within the human tumour microenvironment but this evasion mechanism can be therapeutically targeted, boosting anti-tumour immunity. |
| doi_str_mv | 10.1371/journal.pone.0022842 |
| format | Article |
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In animal models, the activity of cytotoxic lymphocytes is suppressed in the tumour microenvironment by the immunosuppressive cytokine, Transforming Growth Factor (TGF)-[beta]. Release from TGF-[beta]-mediated inhibition restores anti-tumour immunity, suggesting a therapeutic strategy for human cancer. We demonstrate that human natural killer (NK) cells are inhibited in a TGF-[beta] dependent manner following chronic contact-dependent interactions with tumour cells in vitro. In vivo, NK cell inhibition was localised to the human tumour microenvironment and primary ovarian tumours conferred TGF-[beta] dependent inhibition upon autologous NK cells ex vivo. TGF-[beta] antagonized the interleukin (IL)-15 induced proliferation and gene expression associated with NK cell activation, inhibiting the expression of both NK cell activation receptor molecules and components of the cytotoxic apparatus. Interleukin-15 also promotes NK cell survival and IL-15 excluded the pro-apoptotic transcription factor FOXO3 from the nucleus. However, this IL-15 mediated pathway was unaffected by TGF-[beta] treatment, allowing NK cell survival. This suggested that NK cells in the tumour microenvironment might have their activity restored by TGF-[beta] blockade and both anti-TGF-[beta] antibodies and a small molecule inhibitor of TGF-[beta] signalling restored the effector function of NK cells inhibited by autologous tumour cells. Thus, TGF-[beta] blunts NK cell activation within the human tumour microenvironment but this evasion mechanism can be therapeutically targeted, boosting anti-tumour immunity.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0022842</identifier><language>eng</language><publisher>Public Library of Science</publisher><subject>Analysis ; Bone morphogenetic proteins ; Cancer ; Development and progression ; Gene expression ; Genes ; Health aspects ; Immunotherapy ; Interleukins ; Killer cells ; Transforming growth factors</subject><ispartof>PloS one, 2011-09, Vol.6 (9), p.e22842</ispartof><rights>COPYRIGHT 2011 Public Library of Science</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,860,27901,27902</link.rule.ids></links><search><creatorcontrib>Wilson, Erica B</creatorcontrib><creatorcontrib>El-Jawhari, Jehan J</creatorcontrib><creatorcontrib>Neilson, Abbie L</creatorcontrib><creatorcontrib>Hall, Geoffrey D</creatorcontrib><creatorcontrib>Melcher, Alan A</creatorcontrib><creatorcontrib>Meade, Josephine L</creatorcontrib><creatorcontrib>Cook, Graham P</creatorcontrib><title>Human Tumour Immune Evasion via TGF-[beta] Blocks NK Cell Activation but Not Survival Allowing Therapeutic Restoration of Anti-Tumour Activity</title><title>PloS one</title><description>Immune evasion is now recognized as a key feature of cancer progression. In animal models, the activity of cytotoxic lymphocytes is suppressed in the tumour microenvironment by the immunosuppressive cytokine, Transforming Growth Factor (TGF)-[beta]. Release from TGF-[beta]-mediated inhibition restores anti-tumour immunity, suggesting a therapeutic strategy for human cancer. We demonstrate that human natural killer (NK) cells are inhibited in a TGF-[beta] dependent manner following chronic contact-dependent interactions with tumour cells in vitro. In vivo, NK cell inhibition was localised to the human tumour microenvironment and primary ovarian tumours conferred TGF-[beta] dependent inhibition upon autologous NK cells ex vivo. TGF-[beta] antagonized the interleukin (IL)-15 induced proliferation and gene expression associated with NK cell activation, inhibiting the expression of both NK cell activation receptor molecules and components of the cytotoxic apparatus. Interleukin-15 also promotes NK cell survival and IL-15 excluded the pro-apoptotic transcription factor FOXO3 from the nucleus. However, this IL-15 mediated pathway was unaffected by TGF-[beta] treatment, allowing NK cell survival. This suggested that NK cells in the tumour microenvironment might have their activity restored by TGF-[beta] blockade and both anti-TGF-[beta] antibodies and a small molecule inhibitor of TGF-[beta] signalling restored the effector function of NK cells inhibited by autologous tumour cells. Thus, TGF-[beta] blunts NK cell activation within the human tumour microenvironment but this evasion mechanism can be therapeutically targeted, boosting anti-tumour immunity.</description><subject>Analysis</subject><subject>Bone morphogenetic proteins</subject><subject>Cancer</subject><subject>Development and progression</subject><subject>Gene expression</subject><subject>Genes</subject><subject>Health aspects</subject><subject>Immunotherapy</subject><subject>Interleukins</subject><subject>Killer cells</subject><subject>Transforming growth factors</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><recordid>eNqNkM9Kw0AQxoMoqNU38LAgCB5Sd5PsJjnW4p9iUbDVi0jZbCbt6iZbsrtVX8Jndmt7aMGDzGGGmd_3DXxBcEJwl8QpuXjTrm246s51A12MoyhLop3ggORxFLIIx7sb835waMwbxjTOGDsIvm9dzRs0drX3QIO6dg2gqwU3UjdoITka31yHLwVY_ooulRbvBt3foT4ohXrCygW3S7BwFt1ri0auXfidvymlP2QzReMZtHwOzkqBHsFY3a4UukK9xspw_fjXS9qvo2Cv4srA8bp3gqfrq3H_Nhw-3Az6vWE4JYyxsOAJoZDkICgWtOAQkypP8xSXtKooTXORJhBzn0OBMSlLoKQALqBgBYW8hLgTnK58p1zBRDaVti0XtTRi0ktSlmU4w8xT3T8oXyXUUviwK-n3W4LzLYFnLHzaKXfGTAajx_-zD8_b7NkGOwOu7Mxo5ZZRmk3wB854ox0</recordid><startdate>20110906</startdate><enddate>20110906</enddate><creator>Wilson, Erica B</creator><creator>El-Jawhari, Jehan J</creator><creator>Neilson, Abbie L</creator><creator>Hall, Geoffrey D</creator><creator>Melcher, Alan A</creator><creator>Meade, Josephine L</creator><creator>Cook, Graham P</creator><general>Public Library of Science</general><scope>IOV</scope><scope>ISR</scope></search><sort><creationdate>20110906</creationdate><title>Human Tumour Immune Evasion via TGF-[beta] Blocks NK Cell Activation but Not Survival Allowing Therapeutic Restoration of Anti-Tumour Activity</title><author>Wilson, Erica B ; El-Jawhari, Jehan J ; Neilson, Abbie L ; Hall, Geoffrey D ; Melcher, Alan A ; Meade, Josephine L ; Cook, Graham P</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-g1666-ba415e49ec50c5bae31f97970d5ff5579c74e3a284b001dde51beaceb6b5e9de3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Analysis</topic><topic>Bone morphogenetic proteins</topic><topic>Cancer</topic><topic>Development and progression</topic><topic>Gene expression</topic><topic>Genes</topic><topic>Health aspects</topic><topic>Immunotherapy</topic><topic>Interleukins</topic><topic>Killer cells</topic><topic>Transforming growth factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wilson, Erica B</creatorcontrib><creatorcontrib>El-Jawhari, Jehan J</creatorcontrib><creatorcontrib>Neilson, Abbie L</creatorcontrib><creatorcontrib>Hall, Geoffrey D</creatorcontrib><creatorcontrib>Melcher, Alan A</creatorcontrib><creatorcontrib>Meade, Josephine L</creatorcontrib><creatorcontrib>Cook, Graham P</creatorcontrib><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wilson, Erica B</au><au>El-Jawhari, Jehan J</au><au>Neilson, Abbie L</au><au>Hall, Geoffrey D</au><au>Melcher, Alan A</au><au>Meade, Josephine L</au><au>Cook, Graham P</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Human Tumour Immune Evasion via TGF-[beta] Blocks NK Cell Activation but Not Survival Allowing Therapeutic Restoration of Anti-Tumour Activity</atitle><jtitle>PloS one</jtitle><date>2011-09-06</date><risdate>2011</risdate><volume>6</volume><issue>9</issue><spage>e22842</spage><pages>e22842-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Immune evasion is now recognized as a key feature of cancer progression. In animal models, the activity of cytotoxic lymphocytes is suppressed in the tumour microenvironment by the immunosuppressive cytokine, Transforming Growth Factor (TGF)-[beta]. Release from TGF-[beta]-mediated inhibition restores anti-tumour immunity, suggesting a therapeutic strategy for human cancer. We demonstrate that human natural killer (NK) cells are inhibited in a TGF-[beta] dependent manner following chronic contact-dependent interactions with tumour cells in vitro. In vivo, NK cell inhibition was localised to the human tumour microenvironment and primary ovarian tumours conferred TGF-[beta] dependent inhibition upon autologous NK cells ex vivo. TGF-[beta] antagonized the interleukin (IL)-15 induced proliferation and gene expression associated with NK cell activation, inhibiting the expression of both NK cell activation receptor molecules and components of the cytotoxic apparatus. Interleukin-15 also promotes NK cell survival and IL-15 excluded the pro-apoptotic transcription factor FOXO3 from the nucleus. However, this IL-15 mediated pathway was unaffected by TGF-[beta] treatment, allowing NK cell survival. This suggested that NK cells in the tumour microenvironment might have their activity restored by TGF-[beta] blockade and both anti-TGF-[beta] antibodies and a small molecule inhibitor of TGF-[beta] signalling restored the effector function of NK cells inhibited by autologous tumour cells. Thus, TGF-[beta] blunts NK cell activation within the human tumour microenvironment but this evasion mechanism can be therapeutically targeted, boosting anti-tumour immunity.</abstract><pub>Public Library of Science</pub><doi>10.1371/journal.pone.0022842</doi><tpages>e22842</tpages></addata></record> |
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| identifier | ISSN: 1932-6203 |
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| source | DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Analysis Bone morphogenetic proteins Cancer Development and progression Gene expression Genes Health aspects Immunotherapy Interleukins Killer cells Transforming growth factors |
| title | Human Tumour Immune Evasion via TGF-[beta] Blocks NK Cell Activation but Not Survival Allowing Therapeutic Restoration of Anti-Tumour Activity |
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