Improved Treatment of Breast Cancer with Anti-HER2 Therapy Requires Interleukin-21 Signaling in CD8+ T Cells.
Identifieur interne : 002370 ( PubMed/Corpus ); précédent : 002369; suivant : 002371Improved Treatment of Breast Cancer with Anti-HER2 Therapy Requires Interleukin-21 Signaling in CD8+ T Cells.
Auteurs : Deepak Mittal ; Franco Caramia ; Stefan Michiels ; Heikki Joensuu ; Pirkko-Liisa Kellokumpu-Lehtinen ; Christos Sotiriou ; Sherene Loi ; Mark J. SmythSource :
- Cancer research [ 1538-7445 ] ; 2016.
English descriptors
- KwdEn :
- MESH :
- chemical , genetics : Interleukins, Receptor, ErbB-2.
- genetics : Breast Neoplasms.
- immunology : CD8-Positive T-Lymphocytes.
- chemical , metabolism : Receptor, ErbB-2.
- pathology : Breast Neoplasms.
- Animals, Cell Line, Tumor, Disease-Free Survival, Female, Humans, Mice, Mice, Inbred BALB C, Signal Transduction.
Abstract
The HER2/ErbB2 monoclonal antibody (mAb) trastuzumab is combined with chemotherapy as a standard-of-care for newly diagnosed HER2(+) breast cancer patients, but some patients treated with this combination therapy experience early relapse. Our analysis of data from a clinical trial evaluating the efficacy of chemotherapy plus/minus trastuzumab suggested that the magnitude of trastuzumab benefit on distant disease-free survival was higher for increasing expression of the IL21 receptor (IL21R). Therefore, we investigated a possible role for IL21 signaling in promoting HER2 mAb therapeutic efficacy. We found that IL21R-deficient mice and wild-type mice treated with a neutralizing anti-IL21 mAb were less susceptible to trastuzumab-like anti-ErbB2 therapy. Furthermore, IL21R expression on CD8(+) T cells, but not on natural killer cells, was required for optimal anti-ErbB2 mAb efficacy, and IL21 expression was enhanced in tumor-infiltrating CD4(+) T lymphocytes after anti-ErbB2 therapy. Finally, we found that administering recombinant IL21 in combination with anti-ErbB2 therapy was therapeutic against primary tumors and experimental metastases in mice. Collectively, our findings suggest that elevating IL21 signaling may enhance trastuzumab efficacy, thus constituting a novel candidate strategy to overcome trastuzumab resistance and improve patient survival. Cancer
DOI: 10.1158/0008-5472.CAN-15-1567
PubMed: 26744522
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pubmed:26744522Le document en format XML
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School of Medicine, University of Queensland, Herston, Queensland, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Caramia, Franco" sort="Caramia, Franco" uniqKey="Caramia F" first="Franco" last="Caramia">Franco Caramia</name><affiliation><nlm:affiliation>Peter MacCallum Cancer Centre, University of Melbourne, East Melbourne, Victoria, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Michiels, Stefan" sort="Michiels, Stefan" uniqKey="Michiels S" first="Stefan" last="Michiels">Stefan Michiels</name><affiliation><nlm:affiliation>Service de Biostatistique et d'Epidemiologie, Gustave Roussy, Villejuif, France. 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Smyth</name><affiliation><nlm:affiliation>Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. School of Medicine, University of Queensland, Herston, Queensland, Australia. Mark.Smyth@qimrberghofer.edu.au.</nlm:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2016">2016</date><idno type="RBID">pubmed:26744522</idno><idno type="pmid">26744522</idno><idno type="doi">10.1158/0008-5472.CAN-15-1567</idno><idno type="wicri:Area/PubMed/Corpus">002370</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">002370</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Improved Treatment of Breast Cancer with Anti-HER2 Therapy Requires Interleukin-21 Signaling in CD8+ T Cells.</title><author><name sortKey="Mittal, Deepak" sort="Mittal, Deepak" uniqKey="Mittal D" first="Deepak" last="Mittal">Deepak Mittal</name><affiliation><nlm:affiliation>Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. School of Medicine, University of Queensland, Herston, Queensland, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Caramia, Franco" sort="Caramia, Franco" uniqKey="Caramia F" first="Franco" last="Caramia">Franco Caramia</name><affiliation><nlm:affiliation>Peter MacCallum Cancer Centre, University of Melbourne, East Melbourne, Victoria, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Michiels, Stefan" sort="Michiels, Stefan" uniqKey="Michiels S" first="Stefan" last="Michiels">Stefan Michiels</name><affiliation><nlm:affiliation>Service de Biostatistique et d'Epidemiologie, Gustave Roussy, Villejuif, France. INSERM U1018, CESP, Université Paris-Sud, Université Paris-Saclay, Villejuif, France.</nlm:affiliation></affiliation></author><author><name sortKey="Joensuu, Heikki" sort="Joensuu, Heikki" uniqKey="Joensuu H" first="Heikki" last="Joensuu">Heikki Joensuu</name><affiliation><nlm:affiliation>Department of Oncology, Helsinki University Central Hospital and Helsinki University, Helsinki, Finland.</nlm:affiliation></affiliation></author><author><name sortKey="Kellokumpu Lehtinen, Pirkko Liisa" sort="Kellokumpu Lehtinen, Pirkko Liisa" uniqKey="Kellokumpu Lehtinen P" first="Pirkko-Liisa" last="Kellokumpu-Lehtinen">Pirkko-Liisa Kellokumpu-Lehtinen</name><affiliation><nlm:affiliation>Department of Oncology, Tampere University Hospital and Tampere University, Tampere, Finland.</nlm:affiliation></affiliation></author><author><name sortKey="Sotiriou, Christos" sort="Sotiriou, Christos" uniqKey="Sotiriou C" first="Christos" last="Sotiriou">Christos Sotiriou</name><affiliation><nlm:affiliation>Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, Brussels, Belgium.</nlm:affiliation></affiliation></author><author><name sortKey="Loi, Sherene" sort="Loi, Sherene" uniqKey="Loi S" first="Sherene" last="Loi">Sherene Loi</name><affiliation><nlm:affiliation>Peter MacCallum Cancer Centre, University of Melbourne, East Melbourne, Victoria, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Smyth, Mark J" sort="Smyth, Mark J" uniqKey="Smyth M" first="Mark J" last="Smyth">Mark J. Smyth</name><affiliation><nlm:affiliation>Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. School of Medicine, University of Queensland, Herston, Queensland, Australia. Mark.Smyth@qimrberghofer.edu.au.</nlm:affiliation></affiliation></author></analytic><series><title level="j">Cancer research</title><idno type="eISSN">1538-7445</idno><imprint><date when="2016" type="published">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Breast Neoplasms (genetics)</term><term>Breast Neoplasms (pathology)</term><term>CD8-Positive T-Lymphocytes (immunology)</term><term>Cell Line, Tumor</term><term>Disease-Free Survival</term><term>Female</term><term>Humans</term><term>Interleukins (genetics)</term><term>Mice</term><term>Mice, Inbred BALB C</term><term>Receptor, ErbB-2 (genetics)</term><term>Receptor, ErbB-2 (metabolism)</term><term>Signal Transduction</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Interleukins</term><term>Receptor, ErbB-2</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Breast Neoplasms</term></keywords><keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>CD8-Positive T-Lymphocytes</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Receptor, ErbB-2</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Breast Neoplasms</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Cell Line, Tumor</term><term>Disease-Free Survival</term><term>Female</term><term>Humans</term><term>Mice</term><term>Mice, Inbred BALB C</term><term>Signal Transduction</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The HER2/ErbB2 monoclonal antibody (mAb) trastuzumab is combined with chemotherapy as a standard-of-care for newly diagnosed HER2(+) breast cancer patients, but some patients treated with this combination therapy experience early relapse. Our analysis of data from a clinical trial evaluating the efficacy of chemotherapy plus/minus trastuzumab suggested that the magnitude of trastuzumab benefit on distant disease-free survival was higher for increasing expression of the IL21 receptor (IL21R). Therefore, we investigated a possible role for IL21 signaling in promoting HER2 mAb therapeutic efficacy. We found that IL21R-deficient mice and wild-type mice treated with a neutralizing anti-IL21 mAb were less susceptible to trastuzumab-like anti-ErbB2 therapy. Furthermore, IL21R expression on CD8(+) T cells, but not on natural killer cells, was required for optimal anti-ErbB2 mAb efficacy, and IL21 expression was enhanced in tumor-infiltrating CD4(+) T lymphocytes after anti-ErbB2 therapy. Finally, we found that administering recombinant IL21 in combination with anti-ErbB2 therapy was therapeutic against primary tumors and experimental metastases in mice. Collectively, our findings suggest that elevating IL21 signaling may enhance trastuzumab efficacy, thus constituting a novel candidate strategy to overcome trastuzumab resistance and improve patient survival. Cancer</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">26744522</PMID><DateCreated><Year>2016</Year><Month>01</Month><Day>16</Day></DateCreated><DateCompleted><Year>2016</Year><Month>06</Month><Day>28</Day></DateCompleted><DateRevised><Year>2016</Year><Month>01</Month><Day>16</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1538-7445</ISSN><JournalIssue CitedMedium="Internet"><Volume>76</Volume><Issue>2</Issue><PubDate><Year>2016</Year><Month>Jan</Month><Day>15</Day></PubDate></JournalIssue><Title>Cancer research</Title><ISOAbbreviation>Cancer Res.</ISOAbbreviation></Journal><ArticleTitle>Improved Treatment of Breast Cancer with Anti-HER2 Therapy Requires Interleukin-21 Signaling in CD8+ T Cells.</ArticleTitle><Pagination><MedlinePgn>264-74</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1158/0008-5472.CAN-15-1567</ELocationID><Abstract><AbstractText>The HER2/ErbB2 monoclonal antibody (mAb) trastuzumab is combined with chemotherapy as a standard-of-care for newly diagnosed HER2(+) breast cancer patients, but some patients treated with this combination therapy experience early relapse. Our analysis of data from a clinical trial evaluating the efficacy of chemotherapy plus/minus trastuzumab suggested that the magnitude of trastuzumab benefit on distant disease-free survival was higher for increasing expression of the IL21 receptor (IL21R). Therefore, we investigated a possible role for IL21 signaling in promoting HER2 mAb therapeutic efficacy. We found that IL21R-deficient mice and wild-type mice treated with a neutralizing anti-IL21 mAb were less susceptible to trastuzumab-like anti-ErbB2 therapy. Furthermore, IL21R expression on CD8(+) T cells, but not on natural killer cells, was required for optimal anti-ErbB2 mAb efficacy, and IL21 expression was enhanced in tumor-infiltrating CD4(+) T lymphocytes after anti-ErbB2 therapy. Finally, we found that administering recombinant IL21 in combination with anti-ErbB2 therapy was therapeutic against primary tumors and experimental metastases in mice. Collectively, our findings suggest that elevating IL21 signaling may enhance trastuzumab efficacy, thus constituting a novel candidate strategy to overcome trastuzumab resistance and improve patient survival. Cancer</AbstractText><CopyrightInformation>©2016 American Association for Cancer Research.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Mittal</LastName><ForeName>Deepak</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. School of Medicine, University of Queensland, Herston, Queensland, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Caramia</LastName><ForeName>Franco</ForeName><Initials>F</Initials><AffiliationInfo><Affiliation>Peter MacCallum Cancer Centre, University of Melbourne, East Melbourne, Victoria, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Michiels</LastName><ForeName>Stefan</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Service de Biostatistique et d'Epidemiologie, Gustave Roussy, Villejuif, France. INSERM U1018, CESP, Université Paris-Sud, Université Paris-Saclay, Villejuif, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Joensuu</LastName><ForeName>Heikki</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Department of Oncology, Helsinki University Central Hospital and Helsinki University, Helsinki, Finland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kellokumpu-Lehtinen</LastName><ForeName>Pirkko-Liisa</ForeName><Initials>PL</Initials><AffiliationInfo><Affiliation>Department of Oncology, Tampere University Hospital and Tampere University, Tampere, Finland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Sotiriou</LastName><ForeName>Christos</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, Brussels, Belgium.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Loi</LastName><ForeName>Sherene</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Peter MacCallum Cancer Centre, University of Melbourne, East Melbourne, Victoria, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Smyth</LastName><ForeName>Mark J</ForeName><Initials>MJ</Initials><AffiliationInfo><Affiliation>Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. School of Medicine, University of Queensland, Herston, Queensland, Australia. Mark.Smyth@qimrberghofer.edu.au.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2016</Year><Month>01</Month><Day>07</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Cancer Res</MedlineTA><NlmUniqueID>2984705R</NlmUniqueID><ISSNLinking>0008-5472</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D007378">Interleukins</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C416243">interleukin-21</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.10.1</RegistryNumber><NameOfSubstance UI="C508053">ERBB2 protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.10.1</RegistryNumber><NameOfSubstance UI="D018719">Receptor, ErbB-2</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D001943" MajorTopicYN="N">Breast Neoplasms</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName><QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D018414" MajorTopicYN="N">CD8-Positive T-Lymphocytes</DescriptorName><QualifierName UI="Q000276" MajorTopicYN="Y">immunology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D045744" MajorTopicYN="N">Cell Line, Tumor</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D018572" MajorTopicYN="N">Disease-Free Survival</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D007378" MajorTopicYN="N">Interleukins</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008807" MajorTopicYN="N">Mice, Inbred BALB C</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D018719" MajorTopicYN="N">Receptor, ErbB-2</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D015398" MajorTopicYN="N">Signal Transduction</DescriptorName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2015</Year><Month>06</Month><Day>06</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2015</Year><Month>10</Month><Day>23</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2016</Year><Month>1</Month><Day>9</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2016</Year><Month>1</Month><Day>9</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2016</Year><Month>6</Month><Day>29</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">26744522</ArticleId><ArticleId IdType="pii">0008-5472.CAN-15-1567</ArticleId><ArticleId IdType="doi">10.1158/0008-5472.CAN-15-1567</ArticleId></ArticleIdList></PubmedData></pubmed></record>Pour manipuler ce document sous Unix (Dilib)
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