Regulation of autologous immunity to the mouse 5T4 oncofoetal antigen: implications for immunotherapy
Identifieur interne : 001179 ( Istex/Corpus ); précédent : 001178; suivant : 001180Regulation of autologous immunity to the mouse 5T4 oncofoetal antigen: implications for immunotherapy
Auteurs : Fernanda V. Castro ; Mariam Al-Muftah ; Kate Mulryan ; Hui-Rong Jiang ; Jan-Wouter Drijfhout ; Sumia Ali ; Andrzej J. Rutkowski ; Milena Kalaitsidou ; David E. Gilham ; Peter L. SternSource :
- Cancer Immunology, Immunotherapy [ 0340-7004 ] ; 2012-07-01.
English descriptors
- KwdEn :
Abstract
Abstract: Effective vaccination against tumour-associated antigens (TAA) such as the 5T4 oncofoetal glycoprotein may be limited by the nature of the T cell repertoire and the influence of immunomodulatory factors in particular T regulatory cells (Treg). Here, we identified mouse 5T4-specific T cell epitopes using a 5T4 knock out (5T4KO) mouse and evaluated corresponding wild-type (WT) responses as a model to refine and improve immunogenicity. We have shown that 5T4KO mice vaccinated by replication defective adenovirus encoding mouse 5T4 (Adm5T4) generate potent 5T4-specific IFN-γ CD8 and CD4 T cell responses which mediate significant protection against 5T4 positive tumour challenge. 5T4KO CD8 but not CD4 primed T cells also produced IL-17. By contrast, Adm5T4-immunized WT mice showed no tumour protection consistent with only low avidity CD8 IFN-γ, no IL-17 T cell responses and no detectable CD4 T cell effectors producing IFN-γ or IL-17. Treatment with anti-folate receptor 4 (FR4) antibody significantly reduced the frequency of Tregs in WT mice and enhanced 5T4-specific IFN-γ but reduced IL-10 T cell responses but did not reveal IL-17-producing effectors. This altered balance of effectors by treatment with FR4 antibody after Adm5T4 vaccination provided modest protection against autologous B16m5T4 melanoma challenge. The efficacy of 5T4 and some other TAA vaccines may be limited by the combination of TAA-specific T regs, the deletion and/or alternative differentiation of CD4 T cells as well as the absence of distinct subsets of CD8 T cells.
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DOI: 10.1007/s00262-011-1167-3
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ISTEX:8B8A43F5F11228BF5E04690CFC1C84D83668EA91Le document en format XML
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Castro</name><affiliation><mods:affiliation>Immunology Group, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, M20 4BX, Withington, Manchester, UK</mods:affiliation></affiliation></author><author><name sortKey="Al Muftah, Mariam" sort="Al Muftah, Mariam" uniqKey="Al Muftah M" first="Mariam" last="Al-Muftah">Mariam Al-Muftah</name><affiliation><mods:affiliation>Immunology Group, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, M20 4BX, Withington, Manchester, UK</mods:affiliation></affiliation><affiliation><mods:affiliation>Clinical and Experimental Immunotherapy, Medical Oncology, School of Cancer and Enabling Sciences, University of Manchester, Manchester Academic Healthcare Science Centre, Manchester, UK</mods:affiliation></affiliation></author><author><name sortKey="Mulryan, Kate" sort="Mulryan, Kate" uniqKey="Mulryan K" first="Kate" last="Mulryan">Kate Mulryan</name><affiliation><mods:affiliation>Immunology Group, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, M20 4BX, Withington, Manchester, UK</mods:affiliation></affiliation></author><author><name sortKey="Jiang, Hui Rong" sort="Jiang, Hui Rong" uniqKey="Jiang H" first="Hui-Rong" last="Jiang">Hui-Rong Jiang</name><affiliation><mods:affiliation>Immunology Group, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, M20 4BX, Withington, Manchester, UK</mods:affiliation></affiliation><affiliation><mods:affiliation>Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK</mods:affiliation></affiliation></author><author><name sortKey="Drijfhout, Jan Wouter" sort="Drijfhout, Jan Wouter" uniqKey="Drijfhout J" first="Jan-Wouter" last="Drijfhout">Jan-Wouter Drijfhout</name><affiliation><mods:affiliation>Immunohaematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Ali, Sumia" sort="Ali, Sumia" uniqKey="Ali S" first="Sumia" last="Ali">Sumia Ali</name><affiliation><mods:affiliation>Immunology Group, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, M20 4BX, Withington, Manchester, UK</mods:affiliation></affiliation></author><author><name sortKey="Rutkowski, Andrzej J" sort="Rutkowski, Andrzej J" uniqKey="Rutkowski A" first="Andrzej J." last="Rutkowski">Andrzej J. Rutkowski</name><affiliation><mods:affiliation>Immunology Group, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, M20 4BX, Withington, Manchester, UK</mods:affiliation></affiliation></author><author><name sortKey="Kalaitsidou, Milena" sort="Kalaitsidou, Milena" uniqKey="Kalaitsidou M" first="Milena" last="Kalaitsidou">Milena Kalaitsidou</name><affiliation><mods:affiliation>Immunology Group, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, M20 4BX, Withington, Manchester, UK</mods:affiliation></affiliation></author><author><name sortKey="Gilham, David E" sort="Gilham, David E" uniqKey="Gilham D" first="David E." last="Gilham">David E. Gilham</name><affiliation><mods:affiliation>Clinical and Experimental Immunotherapy, Medical Oncology, School of Cancer and Enabling Sciences, University of Manchester, Manchester Academic Healthcare Science Centre, Manchester, UK</mods:affiliation></affiliation></author><author><name sortKey="Stern, Peter L" sort="Stern, Peter L" uniqKey="Stern P" first="Peter L." last="Stern">Peter L. Stern</name><affiliation><mods:affiliation>Immunology Group, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, M20 4BX, Withington, Manchester, UK</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: pstern@picr.man.ac.uk</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Cancer Immunology, Immunotherapy</title><title level="j" type="abbrev">Cancer Immunol Immunother</title><idno type="ISSN">0340-7004</idno><idno type="eISSN">1432-0851</idno><imprint><publisher>Springer-Verlag</publisher><pubPlace>Berlin/Heidelberg</pubPlace><date type="published" when="2012-07-01">2012-07-01</date><biblScope unit="volume">61</biblScope><biblScope unit="issue">7</biblScope><biblScope unit="page" from="1005">1005</biblScope><biblScope unit="page" to="1018">1018</biblScope></imprint><idno type="ISSN">0340-7004</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0340-7004</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>5T4 oncofoetal antigen</term><term>Immunotherapy</term><term>T cell epitopes</term><term>T cell repertoire</term><term>T regulatory cells</term><term>Vaccine</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Abstract: Effective vaccination against tumour-associated antigens (TAA) such as the 5T4 oncofoetal glycoprotein may be limited by the nature of the T cell repertoire and the influence of immunomodulatory factors in particular T regulatory cells (Treg). Here, we identified mouse 5T4-specific T cell epitopes using a 5T4 knock out (5T4KO) mouse and evaluated corresponding wild-type (WT) responses as a model to refine and improve immunogenicity. We have shown that 5T4KO mice vaccinated by replication defective adenovirus encoding mouse 5T4 (Adm5T4) generate potent 5T4-specific IFN-γ CD8 and CD4 T cell responses which mediate significant protection against 5T4 positive tumour challenge. 5T4KO CD8 but not CD4 primed T cells also produced IL-17. By contrast, Adm5T4-immunized WT mice showed no tumour protection consistent with only low avidity CD8 IFN-γ, no IL-17 T cell responses and no detectable CD4 T cell effectors producing IFN-γ or IL-17. Treatment with anti-folate receptor 4 (FR4) antibody significantly reduced the frequency of Tregs in WT mice and enhanced 5T4-specific IFN-γ but reduced IL-10 T cell responses but did not reveal IL-17-producing effectors. This altered balance of effectors by treatment with FR4 antibody after Adm5T4 vaccination provided modest protection against autologous B16m5T4 melanoma challenge. The efficacy of 5T4 and some other TAA vaccines may be limited by the combination of TAA-specific T regs, the deletion and/or alternative differentiation of CD4 T cells as well as the absence of distinct subsets of CD8 T cells.</div></front></TEI><istex><corpusName>springer-journals</corpusName><author><json:item><name>Fernanda V. Castro</name><affiliations><json:string>Immunology Group, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, M20 4BX, Withington, Manchester, UK</json:string></affiliations></json:item><json:item><name>Mariam Al-Muftah</name><affiliations><json:string>Immunology Group, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, M20 4BX, Withington, Manchester, UK</json:string><json:string>Clinical and Experimental Immunotherapy, Medical Oncology, School of Cancer and Enabling Sciences, University of Manchester, Manchester Academic Healthcare Science Centre, Manchester, UK</json:string></affiliations></json:item><json:item><name>Kate Mulryan</name><affiliations><json:string>Immunology Group, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, M20 4BX, Withington, Manchester, UK</json:string></affiliations></json:item><json:item><name>Hui-Rong Jiang</name><affiliations><json:string>Immunology Group, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, M20 4BX, Withington, Manchester, UK</json:string><json:string>Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK</json:string></affiliations></json:item><json:item><name>Jan-Wouter Drijfhout</name><affiliations><json:string>Immunohaematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands</json:string></affiliations></json:item><json:item><name>Sumia Ali</name><affiliations><json:string>Immunology Group, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, M20 4BX, Withington, Manchester, UK</json:string></affiliations></json:item><json:item><name>Andrzej J. Rutkowski</name><affiliations><json:string>Immunology Group, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, M20 4BX, Withington, Manchester, UK</json:string></affiliations></json:item><json:item><name>Milena Kalaitsidou</name><affiliations><json:string>Immunology Group, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, M20 4BX, Withington, Manchester, UK</json:string></affiliations></json:item><json:item><name>David E. Gilham</name><affiliations><json:string>Clinical and Experimental Immunotherapy, Medical Oncology, School of Cancer and Enabling Sciences, University of Manchester, Manchester Academic Healthcare Science Centre, Manchester, UK</json:string></affiliations></json:item><json:item><name>Peter L. Stern</name><affiliations><json:string>Immunology Group, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, M20 4BX, Withington, Manchester, UK</json:string><json:string>E-mail: pstern@picr.man.ac.uk</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>5T4 oncofoetal antigen</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>T cell repertoire</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>T cell epitopes</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>T regulatory cells</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Vaccine</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Immunotherapy</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>FR4 : Folate Receptor 4</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>TAA : Tumour-associated antigens</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Treg : T regulatory cell</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>mAb : Monoclonal antibody</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>IL : Interleukin</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>TCR : T cell Receptor</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>sc : Subcutaneous</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>im : Intramuscular</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>iv : Intravenous</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>CTLA-4 : CTL-associated antigen-4</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>GITR : Glucocorticoid-induced TNF receptor</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>MLR : Mixed leucocyte reaction</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Tc17 : IL-17-producing CD8 T cell</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>CEA : Carcinoembryonic antigen</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>IDO : Indoleamine 2, 3-dioxygenase</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>CDR : Complementary determining region</value></json:item></subject><articleId><json:string>1167</json:string><json:string>s00262-011-1167-3</json:string></articleId><arkIstex>ark:/67375/VQC-0FSHMH9T-6</arkIstex><language><json:string>eng</json:string></language><originalGenre><json:string>OriginalPaper</json:string></originalGenre><abstract>Abstract: Effective vaccination against tumour-associated antigens (TAA) such as the 5T4 oncofoetal glycoprotein may be limited by the nature of the T cell repertoire and the influence of immunomodulatory factors in particular T regulatory cells (Treg). Here, we identified mouse 5T4-specific T cell epitopes using a 5T4 knock out (5T4KO) mouse and evaluated corresponding wild-type (WT) responses as a model to refine and improve immunogenicity. We have shown that 5T4KO mice vaccinated by replication defective adenovirus encoding mouse 5T4 (Adm5T4) generate potent 5T4-specific IFN-γ CD8 and CD4 T cell responses which mediate significant protection against 5T4 positive tumour challenge. 5T4KO CD8 but not CD4 primed T cells also produced IL-17. By contrast, Adm5T4-immunized WT mice showed no tumour protection consistent with only low avidity CD8 IFN-γ, no IL-17 T cell responses and no detectable CD4 T cell effectors producing IFN-γ or IL-17. Treatment with anti-folate receptor 4 (FR4) antibody significantly reduced the frequency of Tregs in WT mice and enhanced 5T4-specific IFN-γ but reduced IL-10 T cell responses but did not reveal IL-17-producing effectors. This altered balance of effectors by treatment with FR4 antibody after Adm5T4 vaccination provided modest protection against autologous B16m5T4 melanoma challenge. The efficacy of 5T4 and some other TAA vaccines may be limited by the combination of TAA-specific T regs, the deletion and/or alternative differentiation of CD4 T cells as well as the absence of distinct subsets of CD8 T cells.</abstract><qualityIndicators><refBibsNative>false</refBibsNative><abstractWordCount>235</abstractWordCount><abstractCharCount>1564</abstractCharCount><keywordCount>22</keywordCount><score>9.82</score><pdfWordCount>8188</pdfWordCount><pdfCharCount>53028</pdfCharCount><pdfVersion>1.4</pdfVersion><pdfPageCount>14</pdfPageCount><pdfPageSize>595.276 x 790.866 pts</pdfPageSize></qualityIndicators><title>Regulation of autologous immunity to the mouse 5T4 oncofoetal antigen: implications for immunotherapy</title><genre><json:string>research-article</json:string></genre><host><title>Cancer Immunology, 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type="first">Fernanda</forename><surname>Castro</surname></persName><affiliation>Immunology Group, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, M20 4BX, Withington, Manchester, UK</affiliation></author><author xml:id="author-0001"><persName><forename type="first">Mariam</forename><surname>Al-Muftah</surname></persName><affiliation>Immunology Group, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, M20 4BX, Withington, Manchester, UK</affiliation><affiliation>Clinical and Experimental Immunotherapy, Medical Oncology, School of Cancer and Enabling Sciences, University of Manchester, Manchester Academic Healthcare Science Centre, Manchester, UK</affiliation></author><author xml:id="author-0002"><persName><forename type="first">Kate</forename><surname>Mulryan</surname></persName><affiliation>Immunology Group, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, M20 4BX, Withington, Manchester, UK</affiliation></author><author xml:id="author-0003"><persName><forename type="first">Hui-Rong</forename><surname>Jiang</surname></persName><affiliation>Immunology Group, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, M20 4BX, Withington, Manchester, UK</affiliation><affiliation>Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK</affiliation></author><author xml:id="author-0004"><persName><forename type="first">Jan-Wouter</forename><surname>Drijfhout</surname></persName><affiliation>Immunohaematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands</affiliation></author><author xml:id="author-0005"><persName><forename type="first">Sumia</forename><surname>Ali</surname></persName><affiliation>Immunology Group, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, M20 4BX, Withington, Manchester, UK</affiliation></author><author xml:id="author-0006"><persName><forename type="first">Andrzej</forename><surname>Rutkowski</surname></persName><affiliation>Immunology Group, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, M20 4BX, Withington, Manchester, UK</affiliation></author><author xml:id="author-0007"><persName><forename type="first">Milena</forename><surname>Kalaitsidou</surname></persName><affiliation>Immunology Group, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, M20 4BX, Withington, Manchester, UK</affiliation></author><author xml:id="author-0008"><persName><forename type="first">David</forename><surname>Gilham</surname></persName><affiliation>Clinical and Experimental Immunotherapy, Medical Oncology, School of Cancer and Enabling Sciences, University of Manchester, Manchester Academic Healthcare Science Centre, Manchester, UK</affiliation></author><author xml:id="author-0009" corresp="yes"><persName><forename type="first">Peter</forename><surname>Stern</surname></persName><email>pstern@picr.man.ac.uk</email><affiliation>Immunology Group, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, M20 4BX, Withington, Manchester, UK</affiliation></author><idno type="istex">8B8A43F5F11228BF5E04690CFC1C84D83668EA91</idno><idno type="ark">ark:/67375/VQC-0FSHMH9T-6</idno><idno type="DOI">10.1007/s00262-011-1167-3</idno><idno type="article-id">1167</idno><idno type="article-id">s00262-011-1167-3</idno></analytic><monogr><title level="j">Cancer Immunology, Immunotherapy</title><title level="j" type="abbrev">Cancer Immunol Immunother</title><idno type="pISSN">0340-7004</idno><idno type="eISSN">1432-0851</idno><idno type="journal-ID">true</idno><idno type="issue-article-count">18</idno><idno type="volume-issue-count">12</idno><imprint><publisher>Springer-Verlag</publisher><pubPlace>Berlin/Heidelberg</pubPlace><date type="published" when="2012-07-01"></date><biblScope unit="volume">61</biblScope><biblScope unit="issue">7</biblScope><biblScope unit="page" from="1005">1005</biblScope><biblScope unit="page" to="1018">1018</biblScope></imprint></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2011-09-15</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Abstract: Effective vaccination against tumour-associated antigens (TAA) such as the 5T4 oncofoetal glycoprotein may be limited by the nature of the T cell repertoire and the influence of immunomodulatory factors in particular T regulatory cells (Treg). Here, we identified mouse 5T4-specific T cell epitopes using a 5T4 knock out (5T4KO) mouse and evaluated corresponding wild-type (WT) responses as a model to refine and improve immunogenicity. We have shown that 5T4KO mice vaccinated by replication defective adenovirus encoding mouse 5T4 (Adm5T4) generate potent 5T4-specific IFN-γ CD8 and CD4 T cell responses which mediate significant protection against 5T4 positive tumour challenge. 5T4KO CD8 but not CD4 primed T cells also produced IL-17. By contrast, Adm5T4-immunized WT mice showed no tumour protection consistent with only low avidity CD8 IFN-γ, no IL-17 T cell responses and no detectable CD4 T cell effectors producing IFN-γ or IL-17. Treatment with anti-folate receptor 4 (FR4) antibody significantly reduced the frequency of Tregs in WT mice and enhanced 5T4-specific IFN-γ but reduced IL-10 T cell responses but did not reveal IL-17-producing effectors. This altered balance of effectors by treatment with FR4 antibody after Adm5T4 vaccination provided modest protection against autologous B16m5T4 melanoma challenge. The efficacy of 5T4 and some other TAA vaccines may be limited by the combination of TAA-specific T regs, the deletion and/or alternative differentiation of CD4 T cells as well as the absence of distinct subsets of CD8 T cells.</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>Keywords</head><item><term>5T4 oncofoetal antigen</term></item><item><term>T cell repertoire</term></item><item><term>T cell epitopes</term></item><item><term>T regulatory cells</term></item><item><term>Vaccine</term></item><item><term>Immunotherapy</term></item></list></keywords></textClass><textClass><keywords scheme="keyword"><list><head>Abbreviations</head><item><term>FR4</term><term>Folate Receptor 4</term></item><item><term>TAA</term><term>Tumour-associated antigens</term></item><item><term>Treg</term><term>T regulatory cell</term></item><item><term>mAb</term><term>Monoclonal antibody</term></item><item><term>IL</term><term>Interleukin</term></item><item><term>TCR</term><term>T cell Receptor</term></item><item><term>sc</term><term>Subcutaneous</term></item><item><term>im</term><term>Intramuscular</term></item><item><term>iv</term><term>Intravenous</term></item><item><term>CTLA-4</term><term>CTL-associated antigen-4</term></item><item><term>GITR</term><term>Glucocorticoid-induced TNF receptor</term></item><item><term>MLR</term><term>Mixed leucocyte reaction</term></item><item><term>Tc17</term><term>IL-17-producing CD8 T cell</term></item><item><term>CEA</term><term>Carcinoembryonic antigen</term></item><item><term>IDO</term><term>Indoleamine 2, 3-dioxygenase</term></item><item><term>CDR</term><term>Complementary determining region</term></item></list></keywords></textClass><textClass><keywords scheme="Journal Subject"><list><head>Medicine & Public Health</head><item><term>Cancer Research</term></item><item><term>Oncology</term></item><item><term>Immunology</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2011-09-15">Created</change><change when="2012-07-01">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/ark:/67375/VQC-0FSHMH9T-6/fulltext.txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus springer-journals not found" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="UTF-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//Springer-Verlag//DTD A++ V2.4//EN" URI="http://devel.springer.de/A++/V2.4/DTD/A++V2.4.dtd" name="istex:docType"></istex:docType><istex:document><Publisher><PublisherInfo><PublisherName>Springer-Verlag</PublisherName><PublisherLocation>Berlin/Heidelberg</PublisherLocation></PublisherInfo><Journal OutputMedium="All"><JournalInfo JournalProductType="ArchiveJournal" NumberingStyle="Unnumbered"><JournalID>262</JournalID><JournalPrintISSN>0340-7004</JournalPrintISSN><JournalElectronicISSN>1432-0851</JournalElectronicISSN><JournalTitle>Cancer Immunology, Immunotherapy</JournalTitle><JournalAbbreviatedTitle>Cancer Immunol Immunother</JournalAbbreviatedTitle><JournalSubjectGroup><JournalSubject Type="Primary">Medicine & Public Health</JournalSubject><JournalSubject Type="Secondary">Cancer Research</JournalSubject><JournalSubject Type="Secondary">Oncology</JournalSubject><JournalSubject Type="Secondary">Immunology</JournalSubject></JournalSubjectGroup></JournalInfo><Volume OutputMedium="All"><VolumeInfo TocLevels="0" VolumeType="Regular"><VolumeIDStart>61</VolumeIDStart><VolumeIDEnd>61</VolumeIDEnd><VolumeIssueCount>12</VolumeIssueCount></VolumeInfo><Issue IssueType="Regular" OutputMedium="All"><IssueInfo IssueType="Regular" TocLevels="0"><IssueIDStart>7</IssueIDStart><IssueIDEnd>7</IssueIDEnd><IssueArticleCount>18</IssueArticleCount><IssueHistory><OnlineDate><Year>2012</Year><Month>6</Month><Day>20</Day></OnlineDate><PrintDate><Year>2012</Year><Month>6</Month><Day>19</Day></PrintDate><CoverDate><Year>2012</Year><Month>7</Month></CoverDate><PricelistYear>2012</PricelistYear></IssueHistory><IssueCopyright><CopyrightHolderName>Springer-Verlag</CopyrightHolderName><CopyrightYear>2012</CopyrightYear></IssueCopyright></IssueInfo><Article ID="s00262-011-1167-3" OutputMedium="All"><ArticleInfo ArticleType="OriginalPaper" ContainsESM="Yes" Language="En" NumberingStyle="Unnumbered" TocLevels="0"><ArticleID>1167</ArticleID><ArticleDOI>10.1007/s00262-011-1167-3</ArticleDOI><ArticleSequenceNumber>6</ArticleSequenceNumber><ArticleTitle Language="En" OutputMedium="All">Regulation of autologous immunity to the mouse 5T4 oncofoetal antigen: implications for immunotherapy</ArticleTitle><ArticleCategory>Original Article</ArticleCategory><ArticleFirstPage>1005</ArticleFirstPage><ArticleLastPage>1018</ArticleLastPage><ArticleHistory><RegistrationDate><Year>2011</Year><Month>11</Month><Day>17</Day></RegistrationDate><Received><Year>2011</Year><Month>9</Month><Day>15</Day></Received><Accepted><Year>2011</Year><Month>11</Month><Day>16</Day></Accepted><OnlineDate><Year>2011</Year><Month>11</Month><Day>30</Day></OnlineDate></ArticleHistory><ArticleCopyright><CopyrightHolderName>Springer-Verlag</CopyrightHolderName><CopyrightYear>2011</CopyrightYear></ArticleCopyright><ArticleGrants Type="Regular"><MetadataGrant Grant="OpenAccess"></MetadataGrant><AbstractGrant Grant="OpenAccess"></AbstractGrant><BodyPDFGrant Grant="Restricted"></BodyPDFGrant><BodyHTMLGrant Grant="Restricted"></BodyHTMLGrant><BibliographyGrant Grant="Restricted"></BibliographyGrant><ESMGrant Grant="Restricted"></ESMGrant></ArticleGrants></ArticleInfo><ArticleHeader><AuthorGroup><Author AffiliationIDS="Aff1"><AuthorName DisplayOrder="Western"><GivenName>Fernanda</GivenName><GivenName>V.</GivenName><FamilyName>Castro</FamilyName></AuthorName></Author><Author AffiliationIDS="Aff1 Aff4"><AuthorName DisplayOrder="Western"><GivenName>Mariam</GivenName><FamilyName>Al-Muftah</FamilyName></AuthorName></Author><Author AffiliationIDS="Aff1"><AuthorName DisplayOrder="Western"><GivenName>Kate</GivenName><FamilyName>Mulryan</FamilyName></AuthorName></Author><Author AffiliationIDS="Aff1 Aff2"><AuthorName DisplayOrder="Western"><GivenName>Hui-Rong</GivenName><FamilyName>Jiang</FamilyName></AuthorName></Author><Author AffiliationIDS="Aff3"><AuthorName DisplayOrder="Western"><GivenName>Jan-Wouter</GivenName><FamilyName>Drijfhout</FamilyName></AuthorName></Author><Author AffiliationIDS="Aff1"><AuthorName DisplayOrder="Western"><GivenName>Sumia</GivenName><FamilyName>Ali</FamilyName></AuthorName></Author><Author AffiliationIDS="Aff1"><AuthorName DisplayOrder="Western"><GivenName>Andrzej</GivenName><GivenName>J.</GivenName><FamilyName>Rutkowski</FamilyName></AuthorName></Author><Author AffiliationIDS="Aff1"><AuthorName DisplayOrder="Western"><GivenName>Milena</GivenName><FamilyName>Kalaitsidou</FamilyName></AuthorName></Author><Author AffiliationIDS="Aff4"><AuthorName DisplayOrder="Western"><GivenName>David</GivenName><GivenName>E.</GivenName><FamilyName>Gilham</FamilyName></AuthorName></Author><Author AffiliationIDS="Aff1" CorrespondingAffiliationID="Aff1"><AuthorName DisplayOrder="Western"><GivenName>Peter</GivenName><GivenName>L.</GivenName><FamilyName>Stern</FamilyName></AuthorName><Contact><Phone>+44-161-4463127</Phone><Fax>+44-1614463109</Fax><Email>pstern@picr.man.ac.uk</Email></Contact></Author><Affiliation ID="Aff1"><OrgDivision>Immunology Group, Paterson Institute for Cancer Research</OrgDivision><OrgName>University of Manchester</OrgName><OrgAddress><Street>Wilmslow Road</Street><City>Withington, Manchester</City><Postcode>M20 4BX</Postcode><Country Code="GB">UK</Country></OrgAddress></Affiliation><Affiliation ID="Aff2"><OrgDivision>Strathclyde Institute of Pharmacy and Biomedical Sciences</OrgDivision><OrgName>University of Strathclyde</OrgName><OrgAddress><City>Glasgow</City><Country Code="GB">UK</Country></OrgAddress></Affiliation><Affiliation ID="Aff3"><OrgDivision>Immunohaematology and Blood Transfusion</OrgDivision><OrgName>Leiden University Medical Center</OrgName><OrgAddress><City>Leiden</City><Country Code="NL">The Netherlands</Country></OrgAddress></Affiliation><Affiliation ID="Aff4"><OrgDivision>Clinical and Experimental Immunotherapy, Medical Oncology, School of Cancer and Enabling Sciences</OrgDivision><OrgName>University of Manchester, Manchester Academic Healthcare Science Centre</OrgName><OrgAddress><City>Manchester</City><Country Code="GB">UK</Country></OrgAddress></Affiliation></AuthorGroup><Abstract ID="Abs1" Language="En" OutputMedium="All"><Heading>Abstract</Heading><Para>Effective vaccination against tumour-associated antigens (TAA) such as the 5T4 oncofoetal glycoprotein may be limited by the nature of the T cell repertoire and the influence of immunomodulatory factors in particular T regulatory cells (Treg). Here, we identified mouse 5T4-specific T cell epitopes using a 5T4 knock out (5T4KO) mouse and evaluated corresponding wild-type (WT) responses as a model to refine and improve immunogenicity. We have shown that 5T4KO mice vaccinated by replication defective adenovirus encoding mouse 5T4 (Adm5T4) generate potent 5T4-specific IFN-γ CD8 and CD4 T cell responses which mediate significant protection against 5T4 positive tumour challenge. 5T4KO CD8 but not CD4 primed T cells also produced IL-17. By contrast, Adm5T4-immunized WT mice showed no tumour protection consistent with only low avidity CD8 IFN-γ, no IL-17 T cell responses and no detectable CD4 T cell effectors producing IFN-γ or IL-17. Treatment with anti-folate receptor 4 (FR4) antibody significantly reduced the frequency of Tregs in WT mice and enhanced 5T4-specific IFN-γ but reduced IL-10 T cell responses but did not reveal IL-17-producing effectors. This altered balance of effectors by treatment with FR4 antibody after Adm5T4 vaccination provided modest protection against autologous B16m5T4 melanoma challenge. The efficacy of 5T4 and some other TAA vaccines may be limited by the combination of TAA-specific T regs, the deletion and/or alternative differentiation of CD4 T cells as well as the absence of distinct subsets of CD8 T cells.</Para></Abstract><KeywordGroup Language="En" OutputMedium="All"><Heading>Keywords</Heading><Keyword>5T4 oncofoetal antigen</Keyword><Keyword>T cell repertoire</Keyword><Keyword>T cell epitopes</Keyword><Keyword>T regulatory cells</Keyword><Keyword>Vaccine</Keyword><Keyword>Immunotherapy</Keyword></KeywordGroup><AbbreviationGroup><Heading>Abbreviations</Heading><DefinitionList><DefinitionListEntry><Term>FR4</Term><Description><Para>Folate Receptor 4</Para></Description></DefinitionListEntry><DefinitionListEntry><Term>TAA</Term><Description><Para>Tumour-associated antigens</Para></Description></DefinitionListEntry><DefinitionListEntry><Term>Treg</Term><Description><Para>T regulatory cell</Para></Description></DefinitionListEntry><DefinitionListEntry><Term>mAb</Term><Description><Para>Monoclonal antibody</Para></Description></DefinitionListEntry><DefinitionListEntry><Term>IL</Term><Description><Para>Interleukin</Para></Description></DefinitionListEntry><DefinitionListEntry><Term>TCR</Term><Description><Para>T cell Receptor</Para></Description></DefinitionListEntry><DefinitionListEntry><Term>sc</Term><Description><Para>Subcutaneous</Para></Description></DefinitionListEntry><DefinitionListEntry><Term>im</Term><Description><Para>Intramuscular</Para></Description></DefinitionListEntry><DefinitionListEntry><Term>iv</Term><Description><Para>Intravenous</Para></Description></DefinitionListEntry><DefinitionListEntry><Term>CTLA-4</Term><Description><Para>CTL-associated antigen-4</Para></Description></DefinitionListEntry><DefinitionListEntry><Term>GITR</Term><Description><Para>Glucocorticoid-induced TNF receptor</Para></Description></DefinitionListEntry><DefinitionListEntry><Term>MLR</Term><Description><Para>Mixed leucocyte reaction</Para></Description></DefinitionListEntry><DefinitionListEntry><Term>Tc17</Term><Description><Para>IL-17-producing CD8 T cell</Para></Description></DefinitionListEntry><DefinitionListEntry><Term>CEA</Term><Description><Para>Carcinoembryonic antigen</Para></Description></DefinitionListEntry><DefinitionListEntry><Term>IDO</Term><Description><Para>Indoleamine 2, 3-dioxygenase</Para></Description></DefinitionListEntry><DefinitionListEntry><Term>CDR</Term><Description><Para>Complementary determining region</Para></Description></DefinitionListEntry></DefinitionList></AbbreviationGroup><ArticleNote Type="ESMHint"><Heading>Electronic supplementary material</Heading><SimplePara>The online version of this article (doi:<ExternalRef><RefSource>10.1007/s00262-011-1167-3</RefSource><RefTarget Address="10.1007/s00262-011-1167-3" TargetType="DOI"></RefTarget></ExternalRef>) contains supplementary material, which is available to authorized users.</SimplePara></ArticleNote></ArticleHeader><NoBody></NoBody></Article></Issue></Volume></Journal></Publisher></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Regulation of autologous immunity to the mouse 5T4 oncofoetal antigen: implications for immunotherapy</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Regulation of autologous immunity to the mouse 5T4 oncofoetal antigen: implications for immunotherapy</title></titleInfo><name type="personal"><namePart type="given">Fernanda</namePart><namePart type="given">V.</namePart><namePart type="family">Castro</namePart><affiliation>Immunology Group, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, M20 4BX, Withington, Manchester, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Mariam</namePart><namePart type="family">Al-Muftah</namePart><affiliation>Immunology Group, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, M20 4BX, Withington, Manchester, UK</affiliation><affiliation>Clinical and Experimental Immunotherapy, Medical Oncology, School of Cancer and Enabling Sciences, University of Manchester, Manchester Academic Healthcare Science Centre, Manchester, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Kate</namePart><namePart type="family">Mulryan</namePart><affiliation>Immunology Group, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, M20 4BX, Withington, Manchester, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Hui-Rong</namePart><namePart type="family">Jiang</namePart><affiliation>Immunology Group, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, M20 4BX, Withington, Manchester, UK</affiliation><affiliation>Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jan-Wouter</namePart><namePart type="family">Drijfhout</namePart><affiliation>Immunohaematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Sumia</namePart><namePart type="family">Ali</namePart><affiliation>Immunology Group, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, M20 4BX, Withington, Manchester, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Andrzej</namePart><namePart type="given">J.</namePart><namePart type="family">Rutkowski</namePart><affiliation>Immunology Group, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, M20 4BX, Withington, Manchester, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Milena</namePart><namePart type="family">Kalaitsidou</namePart><affiliation>Immunology Group, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, M20 4BX, Withington, Manchester, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">David</namePart><namePart type="given">E.</namePart><namePart type="family">Gilham</namePart><affiliation>Clinical and Experimental Immunotherapy, Medical Oncology, School of Cancer and Enabling Sciences, University of Manchester, Manchester Academic Healthcare Science Centre, Manchester, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal" displayLabel="corresp"><namePart type="given">Peter</namePart><namePart type="given">L.</namePart><namePart type="family">Stern</namePart><affiliation>Immunology Group, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, M20 4BX, Withington, Manchester, UK</affiliation><affiliation>E-mail: pstern@picr.man.ac.uk</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="OriginalPaper" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</genre><originInfo><publisher>Springer-Verlag</publisher><place><placeTerm type="text">Berlin/Heidelberg</placeTerm></place><dateCreated encoding="w3cdtf">2011-09-15</dateCreated><dateIssued encoding="w3cdtf">2012-07-01</dateIssued><copyrightDate encoding="w3cdtf">2011</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><abstract lang="en">Abstract: Effective vaccination against tumour-associated antigens (TAA) such as the 5T4 oncofoetal glycoprotein may be limited by the nature of the T cell repertoire and the influence of immunomodulatory factors in particular T regulatory cells (Treg). Here, we identified mouse 5T4-specific T cell epitopes using a 5T4 knock out (5T4KO) mouse and evaluated corresponding wild-type (WT) responses as a model to refine and improve immunogenicity. We have shown that 5T4KO mice vaccinated by replication defective adenovirus encoding mouse 5T4 (Adm5T4) generate potent 5T4-specific IFN-γ CD8 and CD4 T cell responses which mediate significant protection against 5T4 positive tumour challenge. 5T4KO CD8 but not CD4 primed T cells also produced IL-17. By contrast, Adm5T4-immunized WT mice showed no tumour protection consistent with only low avidity CD8 IFN-γ, no IL-17 T cell responses and no detectable CD4 T cell effectors producing IFN-γ or IL-17. Treatment with anti-folate receptor 4 (FR4) antibody significantly reduced the frequency of Tregs in WT mice and enhanced 5T4-specific IFN-γ but reduced IL-10 T cell responses but did not reveal IL-17-producing effectors. This altered balance of effectors by treatment with FR4 antibody after Adm5T4 vaccination provided modest protection against autologous B16m5T4 melanoma challenge. The efficacy of 5T4 and some other TAA vaccines may be limited by the combination of TAA-specific T regs, the deletion and/or alternative differentiation of CD4 T cells as well as the absence of distinct subsets of CD8 T cells.</abstract><note>Original Article</note><subject lang="en"><genre>Keywords</genre><topic>5T4 oncofoetal antigen</topic><topic>T cell repertoire</topic><topic>T cell epitopes</topic><topic>T regulatory cells</topic><topic>Vaccine</topic><topic>Immunotherapy</topic></subject><subject><genre>Abbreviations</genre><topic>FR4 : Folate Receptor 4</topic><topic>TAA : Tumour-associated antigens</topic><topic>Treg : T regulatory cell</topic><topic>mAb : Monoclonal antibody</topic><topic>IL : Interleukin</topic><topic>TCR : T cell Receptor</topic><topic>sc : Subcutaneous</topic><topic>im : Intramuscular</topic><topic>iv : Intravenous</topic><topic>CTLA-4 : CTL-associated antigen-4</topic><topic>GITR : Glucocorticoid-induced TNF receptor</topic><topic>MLR : Mixed leucocyte reaction</topic><topic>Tc17 : IL-17-producing CD8 T cell</topic><topic>CEA : Carcinoembryonic antigen</topic><topic>IDO : Indoleamine 2, 3-dioxygenase</topic><topic>CDR : Complementary determining region</topic></subject><relatedItem type="host"><titleInfo><title>Cancer Immunology, Immunotherapy</title></titleInfo><titleInfo type="abbreviated"><title>Cancer Immunol Immunother</title></titleInfo><genre type="journal" authority="ISTEX" authorityURI="https://publication-type.data.istex.fr" valueURI="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</genre><originInfo><publisher>Springer</publisher><dateIssued encoding="w3cdtf">2012-06-20</dateIssued><copyrightDate encoding="w3cdtf">2012</copyrightDate></originInfo><subject><genre>Medicine & Public Health</genre><topic>Cancer Research</topic><topic>Oncology</topic><topic>Immunology</topic></subject><identifier type="ISSN">0340-7004</identifier><identifier type="eISSN">1432-0851</identifier><identifier type="JournalID">262</identifier><identifier type="IssueArticleCount">18</identifier><identifier type="VolumeIssueCount">12</identifier><part><date>2012</date><detail type="volume"><number>61</number><caption>vol.</caption></detail><detail type="issue"><number>7</number><caption>no.</caption></detail><extent unit="pages"><start>1005</start><end>1018</end></extent></part><recordInfo><recordOrigin>Springer-Verlag, 2012</recordOrigin></recordInfo></relatedItem><identifier type="istex">8B8A43F5F11228BF5E04690CFC1C84D83668EA91</identifier><identifier type="ark">ark:/67375/VQC-0FSHMH9T-6</identifier><identifier type="DOI">10.1007/s00262-011-1167-3</identifier><identifier type="ArticleID">1167</identifier><identifier type="ArticleID">s00262-011-1167-3</identifier><accessCondition type="use and reproduction" contentType="copyright">Springer-Verlag, 2011</accessCondition><recordInfo><recordContentSource authority="ISTEX" authorityURI="https://loaded-corpus.data.istex.fr" valueURI="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-3XSW68JL-F">springer</recordContentSource><recordOrigin>Springer-Verlag, 2011</recordOrigin></recordInfo></mods><json:item><extension>json</extension><original>false</original><mimetype>application/json</mimetype><uri>https://api.istex.fr/ark:/67375/VQC-0FSHMH9T-6/record.json</uri></json:item></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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