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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Anticancer immunotherapy by CTLA-4 blockade: obligatory contribution of IL-2 receptors and negative prognostic impact of soluble CD25</title><author><name sortKey="Hannani, Dalil" sort="Hannani, Dalil" uniqKey="Hannani D" first="Dalil" last="Hannani">Dalil Hannani</name><affiliation><nlm:aff id="aff1"><institution>Gustave Roussy Cancer Campus</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>INSERM U1015</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><institution>Université Paris Sud-XI, Faculté de Médecine</institution>, Le Kremlin Bicêtre,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Vetizou, Marie" sort="Vetizou, Marie" uniqKey="Vetizou M" first="Marie" last="Vétizou">Marie Vétizou</name><affiliation><nlm:aff id="aff1"><institution>Gustave Roussy Cancer Campus</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>INSERM U1015</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><institution>Université Paris Sud-XI, Faculté de Médecine</institution>, Le Kremlin Bicêtre,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Enot, David" sort="Enot, David" uniqKey="Enot D" first="David" last="Enot">David Enot</name><affiliation><nlm:aff id="aff1"><institution>Gustave Roussy Cancer Campus</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff4"><institution>INSERM U848</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff5"><institution>Metabolomics Platform, Institut Gustave Roussy</institution>, Villejuif,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Rusakiewicz, Sylvie" sort="Rusakiewicz, Sylvie" uniqKey="Rusakiewicz S" first="Sylvie" last="Rusakiewicz">Sylvie Rusakiewicz</name><affiliation><nlm:aff id="aff1"><institution>Gustave Roussy Cancer Campus</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>INSERM U1015</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff6"><institution>Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 507</institution>, Villejuif,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Chaput, Nathalie" sort="Chaput, Nathalie" uniqKey="Chaput N" first="Nathalie" last="Chaput">Nathalie Chaput</name><affiliation><nlm:aff id="aff1"><institution>Gustave Roussy Cancer Campus</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>INSERM U1015</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff6"><institution>Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 507</institution>, Villejuif,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Klatzmann, David" sort="Klatzmann, David" uniqKey="Klatzmann D" first="David" last="Klatzmann">David Klatzmann</name><affiliation><nlm:aff id="aff7"><institution>INSERM, Unité Mixte de Recherche_S959, I<sup>3</sup></institution>, Paris,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff8"><institution>Assistance-Publique Hopitaux de Paris, Hôpital Pitié-Salpêtrière, Biotherapy</institution>, Paris,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Desbois, Melanie" sort="Desbois, Melanie" uniqKey="Desbois M" first="Melanie" last="Desbois">Melanie Desbois</name><affiliation><nlm:aff id="aff1"><institution>Gustave Roussy Cancer Campus</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>INSERM U1015</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff6"><institution>Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 507</institution>, Villejuif,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Jacquelot, Nicolas" sort="Jacquelot, Nicolas" uniqKey="Jacquelot N" first="Nicolas" last="Jacquelot">Nicolas Jacquelot</name><affiliation><nlm:aff id="aff1"><institution>Gustave Roussy Cancer Campus</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>INSERM U1015</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><institution>Université Paris Sud-XI, Faculté de Médecine</institution>, Le Kremlin Bicêtre,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Vimond, Nadege" sort="Vimond, Nadege" uniqKey="Vimond N" first="Nadège" last="Vimond">Nadège Vimond</name><affiliation><nlm:aff id="aff1"><institution>Gustave Roussy Cancer Campus</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>INSERM U1015</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff6"><institution>Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 507</institution>, Villejuif,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Chouaib, Salem" sort="Chouaib, Salem" uniqKey="Chouaib S" first="Salem" last="Chouaib">Salem Chouaib</name><affiliation><nlm:aff id="aff9"><institution>INSERM U753</institution>, Villejuif,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Mateus, Christine" sort="Mateus, Christine" uniqKey="Mateus C" first="Christine" last="Mateus">Christine Mateus</name><affiliation><nlm:aff id="aff1"><institution>Gustave Roussy Cancer Campus</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff10"><institution>Department of Medical Oncology, IGR</institution>, Villejuif,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Allison, James P" sort="Allison, James P" uniqKey="Allison J" first="James P" last="Allison">James P. Allison</name><affiliation><nlm:aff id="aff11"><institution>Department of Immunology, MD Anderson Cancer Center</institution>, Houston, TX,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Ribas, Antoni" sort="Ribas, Antoni" uniqKey="Ribas A" first="Antoni" last="Ribas">Antoni Ribas</name><affiliation><nlm:aff id="aff12"><institution>University of California Los Angeles</institution>, Los Angeles, CA,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Wolchok, Jedd D" sort="Wolchok, Jedd D" uniqKey="Wolchok J" first="Jedd D" last="Wolchok">Jedd D. Wolchok</name><affiliation><nlm:aff id="aff13"><institution>Ludwig Center for Cancer Immunotherapy, Department of Immunology, and Department of Medicine, Memorial Sloan-Kettering Cancer Center</institution>, New York, NY,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Yuan, Jianda" sort="Yuan, Jianda" uniqKey="Yuan J" first="Jianda" last="Yuan">Jianda Yuan</name><affiliation><nlm:aff id="aff13"><institution>Ludwig Center for Cancer Immunotherapy, Department of Immunology, and Department of Medicine, Memorial Sloan-Kettering Cancer Center</institution>, New York, NY,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Wong, Philip" sort="Wong, Philip" uniqKey="Wong P" first="Philip" last="Wong">Philip Wong</name><affiliation><nlm:aff id="aff13"><institution>Ludwig Center for Cancer Immunotherapy, Department of Immunology, and Department of Medicine, Memorial Sloan-Kettering Cancer Center</institution>, New York, NY,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Postow, Michael" sort="Postow, Michael" uniqKey="Postow M" first="Michael" last="Postow">Michael Postow</name><affiliation><nlm:aff id="aff13"><institution>Ludwig Center for Cancer Immunotherapy, Department of Immunology, and Department of Medicine, Memorial Sloan-Kettering Cancer Center</institution>, New York, NY,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Mackiewicz, Andrzej" sort="Mackiewicz, Andrzej" uniqKey="Mackiewicz A" first="Andrzej" last="Mackiewicz">Andrzej Mackiewicz</name><affiliation><nlm:aff id="aff14"><institution>Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre</institution>, Poznan,<country>Poland</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff15"><institution>Chair of Medical Biotechnology, Poznan University of Medical Sciences</institution>, Poznan,<country>Poland</country></nlm:aff></affiliation></author><author><name sortKey="Mackiewicz, Jacek" sort="Mackiewicz, Jacek" uniqKey="Mackiewicz J" first="Jacek" last="Mackiewicz">Jacek Mackiewicz</name><affiliation><nlm:aff id="aff14"><institution>Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre</institution>, Poznan,<country>Poland</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff15"><institution>Chair of Medical Biotechnology, Poznan University of Medical Sciences</institution>, Poznan,<country>Poland</country></nlm:aff></affiliation></author><author><name sortKey="Schadendorff, Dirk" sort="Schadendorff, Dirk" uniqKey="Schadendorff D" first="Dirk" last="Schadendorff">Dirk Schadendorff</name><affiliation><nlm:aff id="aff16"><institution>Department of Dermatology, University Hospital Essen</institution>,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Jaeger, Dirk" sort="Jaeger, Dirk" uniqKey="Jaeger D" first="Dirk" last="Jaeger">Dirk Jaeger</name><affiliation><nlm:aff id="aff17"><institution>National Center for Tumor Diseases, University Hospital</institution>, Heidelberg,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Korman, Alan J" sort="Korman, Alan J" uniqKey="Korman A" first="Alan J" last="Korman">Alan J. Korman</name><affiliation><nlm:aff id="aff18"><institution>Bristol-Myers Squibb</institution>, Redwood City, CA,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Bahjat, Keith" sort="Bahjat, Keith" uniqKey="Bahjat K" first="Keith" last="Bahjat">Keith Bahjat</name><affiliation><nlm:aff id="aff19"><institution>Earle A Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center</institution>, Portland, OR,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Maio, Michele" sort="Maio, Michele" uniqKey="Maio M" first="Michele" last="Maio">Michele Maio</name><affiliation><nlm:aff id="aff20"><institution>Medical Oncology and Immunotherapy, Department of Oncology, University Hospital of Siena, Istituto Toscano Tumori</institution>, Siena,<country>Italy</country></nlm:aff></affiliation></author><author><name sortKey="Calabro, Luana" sort="Calabro, Luana" uniqKey="Calabro L" first="Luana" last="Calabro">Luana Calabro</name><affiliation><nlm:aff id="aff20"><institution>Medical Oncology and Immunotherapy, Department of Oncology, University Hospital of Siena, Istituto Toscano Tumori</institution>, Siena,<country>Italy</country></nlm:aff></affiliation></author><author><name sortKey="Teng, Michele Wl" sort="Teng, Michele Wl" uniqKey="Teng M" first="Michele Wl" last="Teng">Michele Wl Teng</name><affiliation><nlm:aff id="aff21"><institution>QIMR Berghofer Medical Research Institute</institution>, Herston, 4006, Queensland,<country>Australia</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff22"><institution>School of Medicine, The University of Queensland</institution>, Herston, QLD 4006, Queensland,<country>Australia</country></nlm:aff></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:aff id="aff21"><institution>QIMR Berghofer Medical Research Institute</institution>, Herston, 4006, Queensland,<country>Australia</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff22"><institution>School of Medicine, The University of Queensland</institution>, Herston, QLD 4006, Queensland,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Eggermont, Alexander" sort="Eggermont, Alexander" uniqKey="Eggermont A" first="Alexander" last="Eggermont">Alexander Eggermont</name><affiliation><nlm:aff id="aff1"><institution>Gustave Roussy Cancer Campus</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>INSERM U1015</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff23"><institution>INSERM U981</institution>, Villejuif,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Robert, Caroline" sort="Robert, Caroline" uniqKey="Robert C" first="Caroline" last="Robert">Caroline Robert</name><affiliation><nlm:aff id="aff1"><institution>Gustave Roussy Cancer Campus</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>INSERM U1015</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff10"><institution>Department of Medical Oncology, IGR</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff23"><institution>INSERM U981</institution>, Villejuif,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Kroemer, Guido" sort="Kroemer, Guido" uniqKey="Kroemer G" first="Guido" last="Kroemer">Guido Kroemer</name><affiliation><nlm:aff id="aff1"><institution>Gustave Roussy Cancer Campus</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff4"><institution>INSERM U848</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff5"><institution>Metabolomics Platform, Institut Gustave Roussy</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff24"><institution>Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U 1138</institution>, Paris,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff25"><institution>Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP</institution>, Paris,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff26"><institution>Université Paris Descartes, Sorbonne Paris Cité</institution>, Paris,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Zitvogel, Laurence" sort="Zitvogel, Laurence" uniqKey="Zitvogel L" first="Laurence" last="Zitvogel">Laurence Zitvogel</name><affiliation><nlm:aff id="aff1"><institution>Gustave Roussy Cancer Campus</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>INSERM U1015</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><institution>Université Paris Sud-XI, Faculté de Médecine</institution>, Le Kremlin Bicêtre,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff10"><institution>Department of Medical Oncology, IGR</institution>, Villejuif,<country>France</country></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">25582080</idno><idno type="pmc">4650573</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4650573</idno><idno type="RBID">PMC:4650573</idno><idno type="doi">10.1038/cr.2015.3</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">000695</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000695</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Anticancer immunotherapy by CTLA-4 blockade: obligatory contribution of IL-2 receptors and negative prognostic impact of soluble CD25</title><author><name sortKey="Hannani, Dalil" sort="Hannani, Dalil" uniqKey="Hannani D" first="Dalil" last="Hannani">Dalil Hannani</name><affiliation><nlm:aff id="aff1"><institution>Gustave Roussy Cancer Campus</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>INSERM U1015</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><institution>Université Paris Sud-XI, Faculté de Médecine</institution>, Le Kremlin Bicêtre,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Vetizou, Marie" sort="Vetizou, Marie" uniqKey="Vetizou M" first="Marie" last="Vétizou">Marie Vétizou</name><affiliation><nlm:aff id="aff1"><institution>Gustave Roussy Cancer Campus</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>INSERM U1015</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><institution>Université Paris Sud-XI, Faculté de Médecine</institution>, Le Kremlin Bicêtre,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Enot, David" sort="Enot, David" uniqKey="Enot D" first="David" last="Enot">David Enot</name><affiliation><nlm:aff id="aff1"><institution>Gustave Roussy Cancer Campus</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff4"><institution>INSERM U848</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff5"><institution>Metabolomics Platform, Institut Gustave Roussy</institution>, Villejuif,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Rusakiewicz, Sylvie" sort="Rusakiewicz, Sylvie" uniqKey="Rusakiewicz S" first="Sylvie" last="Rusakiewicz">Sylvie Rusakiewicz</name><affiliation><nlm:aff id="aff1"><institution>Gustave Roussy Cancer Campus</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>INSERM U1015</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff6"><institution>Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 507</institution>, Villejuif,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Chaput, Nathalie" sort="Chaput, Nathalie" uniqKey="Chaput N" first="Nathalie" last="Chaput">Nathalie Chaput</name><affiliation><nlm:aff id="aff1"><institution>Gustave Roussy Cancer Campus</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>INSERM U1015</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff6"><institution>Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 507</institution>, Villejuif,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Klatzmann, David" sort="Klatzmann, David" uniqKey="Klatzmann D" first="David" last="Klatzmann">David Klatzmann</name><affiliation><nlm:aff id="aff7"><institution>INSERM, Unité Mixte de Recherche_S959, I<sup>3</sup></institution>, Paris,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff8"><institution>Assistance-Publique Hopitaux de Paris, Hôpital Pitié-Salpêtrière, Biotherapy</institution>, Paris,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Desbois, Melanie" sort="Desbois, Melanie" uniqKey="Desbois M" first="Melanie" last="Desbois">Melanie Desbois</name><affiliation><nlm:aff id="aff1"><institution>Gustave Roussy Cancer Campus</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>INSERM U1015</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff6"><institution>Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 507</institution>, Villejuif,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Jacquelot, Nicolas" sort="Jacquelot, Nicolas" uniqKey="Jacquelot N" first="Nicolas" last="Jacquelot">Nicolas Jacquelot</name><affiliation><nlm:aff id="aff1"><institution>Gustave Roussy Cancer Campus</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>INSERM U1015</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><institution>Université Paris Sud-XI, Faculté de Médecine</institution>, Le Kremlin Bicêtre,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Vimond, Nadege" sort="Vimond, Nadege" uniqKey="Vimond N" first="Nadège" last="Vimond">Nadège Vimond</name><affiliation><nlm:aff id="aff1"><institution>Gustave Roussy Cancer Campus</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>INSERM U1015</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff6"><institution>Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 507</institution>, Villejuif,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Chouaib, Salem" sort="Chouaib, Salem" uniqKey="Chouaib S" first="Salem" last="Chouaib">Salem Chouaib</name><affiliation><nlm:aff id="aff9"><institution>INSERM U753</institution>, Villejuif,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Mateus, Christine" sort="Mateus, Christine" uniqKey="Mateus C" first="Christine" last="Mateus">Christine Mateus</name><affiliation><nlm:aff id="aff1"><institution>Gustave Roussy Cancer Campus</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff10"><institution>Department of Medical Oncology, IGR</institution>, Villejuif,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Allison, James P" sort="Allison, James P" uniqKey="Allison J" first="James P" last="Allison">James P. Allison</name><affiliation><nlm:aff id="aff11"><institution>Department of Immunology, MD Anderson Cancer Center</institution>, Houston, TX,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Ribas, Antoni" sort="Ribas, Antoni" uniqKey="Ribas A" first="Antoni" last="Ribas">Antoni Ribas</name><affiliation><nlm:aff id="aff12"><institution>University of California Los Angeles</institution>, Los Angeles, CA,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Wolchok, Jedd D" sort="Wolchok, Jedd D" uniqKey="Wolchok J" first="Jedd D" last="Wolchok">Jedd D. Wolchok</name><affiliation><nlm:aff id="aff13"><institution>Ludwig Center for Cancer Immunotherapy, Department of Immunology, and Department of Medicine, Memorial Sloan-Kettering Cancer Center</institution>, New York, NY,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Yuan, Jianda" sort="Yuan, Jianda" uniqKey="Yuan J" first="Jianda" last="Yuan">Jianda Yuan</name><affiliation><nlm:aff id="aff13"><institution>Ludwig Center for Cancer Immunotherapy, Department of Immunology, and Department of Medicine, Memorial Sloan-Kettering Cancer Center</institution>, New York, NY,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Wong, Philip" sort="Wong, Philip" uniqKey="Wong P" first="Philip" last="Wong">Philip Wong</name><affiliation><nlm:aff id="aff13"><institution>Ludwig Center for Cancer Immunotherapy, Department of Immunology, and Department of Medicine, Memorial Sloan-Kettering Cancer Center</institution>, New York, NY,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Postow, Michael" sort="Postow, Michael" uniqKey="Postow M" first="Michael" last="Postow">Michael Postow</name><affiliation><nlm:aff id="aff13"><institution>Ludwig Center for Cancer Immunotherapy, Department of Immunology, and Department of Medicine, Memorial Sloan-Kettering Cancer Center</institution>, New York, NY,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Mackiewicz, Andrzej" sort="Mackiewicz, Andrzej" uniqKey="Mackiewicz A" first="Andrzej" last="Mackiewicz">Andrzej Mackiewicz</name><affiliation><nlm:aff id="aff14"><institution>Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre</institution>, Poznan,<country>Poland</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff15"><institution>Chair of Medical Biotechnology, Poznan University of Medical Sciences</institution>, Poznan,<country>Poland</country></nlm:aff></affiliation></author><author><name sortKey="Mackiewicz, Jacek" sort="Mackiewicz, Jacek" uniqKey="Mackiewicz J" first="Jacek" last="Mackiewicz">Jacek Mackiewicz</name><affiliation><nlm:aff id="aff14"><institution>Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre</institution>, Poznan,<country>Poland</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff15"><institution>Chair of Medical Biotechnology, Poznan University of Medical Sciences</institution>, Poznan,<country>Poland</country></nlm:aff></affiliation></author><author><name sortKey="Schadendorff, Dirk" sort="Schadendorff, Dirk" uniqKey="Schadendorff D" first="Dirk" last="Schadendorff">Dirk Schadendorff</name><affiliation><nlm:aff id="aff16"><institution>Department of Dermatology, University Hospital Essen</institution>,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Jaeger, Dirk" sort="Jaeger, Dirk" uniqKey="Jaeger D" first="Dirk" last="Jaeger">Dirk Jaeger</name><affiliation><nlm:aff id="aff17"><institution>National Center for Tumor Diseases, University Hospital</institution>, Heidelberg,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Korman, Alan J" sort="Korman, Alan J" uniqKey="Korman A" first="Alan J" last="Korman">Alan J. Korman</name><affiliation><nlm:aff id="aff18"><institution>Bristol-Myers Squibb</institution>, Redwood City, CA,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Bahjat, Keith" sort="Bahjat, Keith" uniqKey="Bahjat K" first="Keith" last="Bahjat">Keith Bahjat</name><affiliation><nlm:aff id="aff19"><institution>Earle A Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center</institution>, Portland, OR,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Maio, Michele" sort="Maio, Michele" uniqKey="Maio M" first="Michele" last="Maio">Michele Maio</name><affiliation><nlm:aff id="aff20"><institution>Medical Oncology and Immunotherapy, Department of Oncology, University Hospital of Siena, Istituto Toscano Tumori</institution>, Siena,<country>Italy</country></nlm:aff></affiliation></author><author><name sortKey="Calabro, Luana" sort="Calabro, Luana" uniqKey="Calabro L" first="Luana" last="Calabro">Luana Calabro</name><affiliation><nlm:aff id="aff20"><institution>Medical Oncology and Immunotherapy, Department of Oncology, University Hospital of Siena, Istituto Toscano Tumori</institution>, Siena,<country>Italy</country></nlm:aff></affiliation></author><author><name sortKey="Teng, Michele Wl" sort="Teng, Michele Wl" uniqKey="Teng M" first="Michele Wl" last="Teng">Michele Wl Teng</name><affiliation><nlm:aff id="aff21"><institution>QIMR Berghofer Medical Research Institute</institution>, Herston, 4006, Queensland,<country>Australia</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff22"><institution>School of Medicine, The University of Queensland</institution>, Herston, QLD 4006, Queensland,<country>Australia</country></nlm:aff></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:aff id="aff21"><institution>QIMR Berghofer Medical Research Institute</institution>, Herston, 4006, Queensland,<country>Australia</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff22"><institution>School of Medicine, The University of Queensland</institution>, Herston, QLD 4006, Queensland,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Eggermont, Alexander" sort="Eggermont, Alexander" uniqKey="Eggermont A" first="Alexander" last="Eggermont">Alexander Eggermont</name><affiliation><nlm:aff id="aff1"><institution>Gustave Roussy Cancer Campus</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>INSERM U1015</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff23"><institution>INSERM U981</institution>, Villejuif,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Robert, Caroline" sort="Robert, Caroline" uniqKey="Robert C" first="Caroline" last="Robert">Caroline Robert</name><affiliation><nlm:aff id="aff1"><institution>Gustave Roussy Cancer Campus</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>INSERM U1015</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff10"><institution>Department of Medical Oncology, IGR</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff23"><institution>INSERM U981</institution>, Villejuif,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Kroemer, Guido" sort="Kroemer, Guido" uniqKey="Kroemer G" first="Guido" last="Kroemer">Guido Kroemer</name><affiliation><nlm:aff id="aff1"><institution>Gustave Roussy Cancer Campus</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff4"><institution>INSERM U848</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff5"><institution>Metabolomics Platform, Institut Gustave Roussy</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff24"><institution>Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U 1138</institution>, Paris,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff25"><institution>Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP</institution>, Paris,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff26"><institution>Université Paris Descartes, Sorbonne Paris Cité</institution>, Paris,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Zitvogel, Laurence" sort="Zitvogel, Laurence" uniqKey="Zitvogel L" first="Laurence" last="Zitvogel">Laurence Zitvogel</name><affiliation><nlm:aff id="aff1"><institution>Gustave Roussy Cancer Campus</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>INSERM U1015</institution>, Villejuif,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><institution>Université Paris Sud-XI, Faculté de Médecine</institution>, Le Kremlin Bicêtre,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff10"><institution>Department of Medical Oncology, IGR</institution>, Villejuif,<country>France</country></nlm:aff></affiliation></author></analytic><series><title level="j">Cell Research</title><idno type="ISSN">1001-0602</idno><idno type="eISSN">1748-7838</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>The cytotoxic T lymphocyte antigen-4 (CTLA-4)-blocking antibody ipilimumab induces immune-mediated long-term control of metastatic melanoma in a fraction of patients. Although ipilimumab undoubtedly exerts its therapeutic effects via immunostimulation, thus far clinically useful, immunologically relevant biomarkers that predict treatment efficiency have been elusive. Here, we show that neutralization of IL-2 or blocking the α and β subunits of the IL-2 receptor (CD25 and CD122, respectively) abolished the antitumor effects and the accompanying improvement of the ratio of intratumoral T effector versus regulatory cells (Tregs), which were otherwise induced by CTLA-4 blockade in preclinical mouse models. CTLA-4 blockade led to the reduction of a suppressive CD4<sup>+</sup> T cell subset expressing Lag3, ICOS, IL-10 and Egr2 with a concomitant rise in IL-2-producing effector cells that lost FoxP3 expression and accumulated in regressing tumors. While recombinant IL-2 improved the therapeutic efficacy of CTLA-4 blockade, the decoy IL-2 receptor α (IL-2Rα, sCD25) inhibited the anticancer effects of CTLA-4 blockade. In 262 metastatic melanoma patients receiving ipilimumab, baseline serum concentrations of sCD25 represented an independent indicator of overall survival, with high levels predicting resistance to therapy. Altogether, these results unravel a role for IL-2 and IL-2 receptors in the anticancer activity of CTLA-4 blockade. Importantly, our study provides the first immunologically relevant biomarker, namely elevated serum sCD25, that predicts resistance to CTLA-4 blockade in patients with melanoma.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Cell Res</journal-id><journal-id journal-id-type="iso-abbrev">Cell Res</journal-id><journal-title-group><journal-title>Cell Research</journal-title></journal-title-group><issn pub-type="ppub">1001-0602</issn><issn pub-type="epub">1748-7838</issn><publisher><publisher-name>Nature Publishing Group</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">25582080</article-id><article-id pub-id-type="pmc">4650573</article-id><article-id pub-id-type="pii">cr20153</article-id><article-id pub-id-type="doi">10.1038/cr.2015.3</article-id><article-categories><subj-group subj-group-type="heading"><subject>Original Article</subject></subj-group></article-categories><title-group><article-title>Anticancer immunotherapy by CTLA-4 blockade: obligatory contribution of IL-2 receptors and negative prognostic impact of soluble CD25</article-title><alt-title alt-title-type="running">sCD25 and ipilimumab</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Hannani</surname><given-names>Dalil</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref><xref ref-type="aff" rid="aff3">3</xref><xref ref-type="author-notes" rid="note1"><sup>*</sup></xref></contrib><contrib contrib-type="author"><name><surname>Vétizou</surname><given-names>Marie</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref><xref ref-type="aff" rid="aff3">3</xref><xref ref-type="author-notes" rid="note1"><sup>*</sup></xref></contrib><contrib contrib-type="author"><name><surname>Enot</surname><given-names>David</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff4">4</xref><xref ref-type="aff" rid="aff5">5</xref></contrib><contrib contrib-type="author"><name><surname>Rusakiewicz</surname><given-names>Sylvie</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref><xref ref-type="aff" rid="aff6">6</xref></contrib><contrib contrib-type="author"><name><surname>Chaput</surname><given-names>Nathalie</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref><xref ref-type="aff" rid="aff6">6</xref></contrib><contrib contrib-type="author"><name><surname>Klatzmann</surname><given-names>David</given-names></name><xref ref-type="aff" rid="aff7">7</xref><xref ref-type="aff" rid="aff8">8</xref></contrib><contrib contrib-type="author"><name><surname>Desbois</surname><given-names>Melanie</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref><xref ref-type="aff" rid="aff6">6</xref></contrib><contrib contrib-type="author"><name><surname>Jacquelot</surname><given-names>Nicolas</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref><xref ref-type="aff" rid="aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Vimond</surname><given-names>Nadège</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref><xref ref-type="aff" rid="aff6">6</xref></contrib><contrib contrib-type="author"><name><surname>Chouaib</surname><given-names>Salem</given-names></name><xref ref-type="aff" rid="aff9">9</xref></contrib><contrib contrib-type="author"><name><surname>Mateus</surname><given-names>Christine</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff10">10</xref></contrib><contrib contrib-type="author"><name><surname>Allison</surname><given-names>James P</given-names></name><xref ref-type="aff" rid="aff11">11</xref></contrib><contrib contrib-type="author"><name><surname>Ribas</surname><given-names>Antoni</given-names></name><xref ref-type="aff" rid="aff12">12</xref></contrib><contrib contrib-type="author"><name><surname>Wolchok</surname><given-names>Jedd D</given-names></name><xref ref-type="aff" rid="aff13">13</xref></contrib><contrib contrib-type="author"><name><surname>Yuan</surname><given-names>Jianda</given-names></name><xref ref-type="aff" rid="aff13">13</xref></contrib><contrib contrib-type="author"><name><surname>Wong</surname><given-names>Philip</given-names></name><xref ref-type="aff" rid="aff13">13</xref></contrib><contrib contrib-type="author"><name><surname>Postow</surname><given-names>Michael</given-names></name><xref ref-type="aff" rid="aff13">13</xref></contrib><contrib contrib-type="author"><name><surname>Mackiewicz</surname><given-names>Andrzej</given-names></name><xref ref-type="aff" rid="aff14">14</xref><xref ref-type="aff" rid="aff15">15</xref></contrib><contrib contrib-type="author"><name><surname>Mackiewicz</surname><given-names>Jacek</given-names></name><xref ref-type="aff" rid="aff14">14</xref><xref ref-type="aff" rid="aff15">15</xref></contrib><contrib contrib-type="author"><name><surname>Schadendorff</surname><given-names>Dirk</given-names></name><xref ref-type="aff" rid="aff16">16</xref></contrib><contrib contrib-type="author"><name><surname>Jaeger</surname><given-names>Dirk</given-names></name><xref ref-type="aff" rid="aff17">17</xref></contrib><contrib contrib-type="author"><name><surname>Korman</surname><given-names>Alan J</given-names></name><xref ref-type="aff" rid="aff18">18</xref></contrib><contrib contrib-type="author"><name><surname>Bahjat</surname><given-names>Keith</given-names></name><xref ref-type="aff" rid="aff19">19</xref></contrib><contrib contrib-type="author"><name><surname>Maio</surname><given-names>Michele</given-names></name><xref ref-type="aff" rid="aff20">20</xref></contrib><contrib contrib-type="author"><name><surname>Calabro</surname><given-names>Luana</given-names></name><xref ref-type="aff" rid="aff20">20</xref></contrib><contrib contrib-type="author"><name><surname>Teng</surname><given-names>Michele WL</given-names></name><xref ref-type="aff" rid="aff21">21</xref><xref ref-type="aff" rid="aff22">22</xref></contrib><contrib contrib-type="author"><name><surname>Smyth</surname><given-names>Mark J</given-names></name><xref ref-type="aff" rid="aff21">21</xref><xref ref-type="aff" rid="aff22">22</xref></contrib><contrib contrib-type="author"><name><surname>Eggermont</surname><given-names>Alexander</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref><xref ref-type="aff" rid="aff23">23</xref></contrib><contrib contrib-type="author"><name><surname>Robert</surname><given-names>Caroline</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref><xref ref-type="aff" rid="aff10">10</xref><xref ref-type="aff" rid="aff23">23</xref></contrib><contrib contrib-type="author"><name><surname>Kroemer</surname><given-names>Guido</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff4">4</xref><xref ref-type="aff" rid="aff5">5</xref><xref ref-type="aff" rid="aff24">24</xref><xref ref-type="aff" rid="aff25">25</xref><xref ref-type="aff" rid="aff26">26</xref><xref ref-type="corresp" rid="caf2">*</xref></contrib><contrib contrib-type="author"><name><surname>Zitvogel</surname><given-names>Laurence</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref><xref ref-type="aff" rid="aff3">3</xref><xref ref-type="aff" rid="aff10">10</xref><xref ref-type="corresp" rid="caf1">*</xref></contrib><aff id="aff1"><label>1</label><institution>Gustave Roussy Cancer Campus</institution>, Villejuif,<country>France</country></aff><aff id="aff2"><label>2</label><institution>INSERM U1015</institution>, Villejuif,<country>France</country></aff><aff id="aff3"><label>3</label><institution>Université Paris Sud-XI, Faculté de Médecine</institution>, Le Kremlin Bicêtre,<country>France</country></aff><aff id="aff4"><label>4</label><institution>INSERM U848</institution>, Villejuif,<country>France</country></aff><aff id="aff5"><label>5</label><institution>Metabolomics Platform, Institut Gustave Roussy</institution>, Villejuif,<country>France</country></aff><aff id="aff6"><label>6</label><institution>Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 507</institution>, Villejuif,<country>France</country></aff><aff id="aff7"><label>7</label><institution>INSERM, Unité Mixte de Recherche_S959, I<sup>3</sup></institution>, Paris,<country>France</country></aff><aff id="aff8"><label>8</label><institution>Assistance-Publique Hopitaux de Paris, Hôpital Pitié-Salpêtrière, Biotherapy</institution>, Paris,<country>France</country></aff><aff id="aff9"><label>9</label><institution>INSERM U753</institution>, Villejuif,<country>France</country></aff><aff id="aff10"><label>10</label><institution>Department of Medical Oncology, IGR</institution>, Villejuif,<country>France</country></aff><aff id="aff11"><label>11</label><institution>Department of Immunology, MD Anderson Cancer Center</institution>, Houston, TX,<country>USA</country></aff><aff id="aff12"><label>12</label><institution>University of California Los Angeles</institution>, Los Angeles, CA,<country>USA</country></aff><aff id="aff13"><label>13</label><institution>Ludwig Center for Cancer Immunotherapy, Department of Immunology, and Department of Medicine, Memorial Sloan-Kettering Cancer Center</institution>, New York, NY,<country>USA</country></aff><aff id="aff14"><label>14</label><institution>Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre</institution>, Poznan,<country>Poland</country></aff><aff id="aff15"><label>15</label><institution>Chair of Medical Biotechnology, Poznan University of Medical Sciences</institution>, Poznan,<country>Poland</country></aff><aff id="aff16"><label>16</label><institution>Department of Dermatology, University Hospital Essen</institution>,<country>Germany</country></aff><aff id="aff17"><label>17</label><institution>National Center for Tumor Diseases, University Hospital</institution>, Heidelberg,<country>Germany</country></aff><aff id="aff18"><label>18</label><institution>Bristol-Myers Squibb</institution>, Redwood City, CA,<country>USA</country></aff><aff id="aff19"><label>19</label><institution>Earle A Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center</institution>, Portland, OR,<country>USA</country></aff><aff id="aff20"><label>20</label><institution>Medical Oncology and Immunotherapy, Department of Oncology, University Hospital of Siena, Istituto Toscano Tumori</institution>, Siena,<country>Italy</country></aff><aff id="aff21"><label>21</label><institution>QIMR Berghofer Medical Research Institute</institution>, Herston, 4006, Queensland,<country>Australia</country></aff><aff id="aff22"><label>22</label><institution>School of Medicine, The University of Queensland</institution>, Herston, QLD 4006, Queensland,<country>Australia</country></aff><aff id="aff23"><label>23</label><institution>INSERM U981</institution>, Villejuif,<country>France</country></aff><aff id="aff24"><label>24</label><institution>Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U 1138</institution>, Paris,<country>France</country></aff><aff id="aff25"><label>25</label><institution>Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP</institution>, Paris,<country>France</country></aff><aff id="aff26"><label>26</label><institution>Université Paris Descartes, Sorbonne Paris Cité</institution>, Paris,<country>France</country></aff></contrib-group><author-notes><corresp id="caf1"><label>*</label>E-mail: <email>laurence.zitvogel@gustaveroussy.fr</email></corresp><corresp id="caf2"><label>*</label>E-mail: <email>kroemer@orange.fr</email></corresp><fn fn-type="present-address" id="note1"><label>*</label><p>These two authors contributed equally to this work.</p></fn></author-notes><pub-date pub-type="ppub"><month>02</month><year>2015</year></pub-date><pub-date pub-type="epub"><day>13</day><month>01</month><year>2015</year></pub-date><volume>25</volume><issue>2</issue><fpage>208</fpage><lpage>224</lpage><history><date date-type="received"><day>22</day><month>05</month><year>2014</year></date><date date-type="rev-recd"><day>13</day><month>08</month><year>2014</year></date><date date-type="accepted"><day>11</day><month>09</month><year>2014</year></date></history><permissions><copyright-statement>Copyright © 2015 Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences</copyright-statement><copyright-year>2015</copyright-year><copyright-holder>Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences</copyright-holder></permissions><abstract><p>The cytotoxic T lymphocyte antigen-4 (CTLA-4)-blocking antibody ipilimumab induces immune-mediated long-term control of metastatic melanoma in a fraction of patients. Although ipilimumab undoubtedly exerts its therapeutic effects via immunostimulation, thus far clinically useful, immunologically relevant biomarkers that predict treatment efficiency have been elusive. Here, we show that neutralization of IL-2 or blocking the α and β subunits of the IL-2 receptor (CD25 and CD122, respectively) abolished the antitumor effects and the accompanying improvement of the ratio of intratumoral T effector versus regulatory cells (Tregs), which were otherwise induced by CTLA-4 blockade in preclinical mouse models. CTLA-4 blockade led to the reduction of a suppressive CD4<sup>+</sup> T cell subset expressing Lag3, ICOS, IL-10 and Egr2 with a concomitant rise in IL-2-producing effector cells that lost FoxP3 expression and accumulated in regressing tumors. While recombinant IL-2 improved the therapeutic efficacy of CTLA-4 blockade, the decoy IL-2 receptor α (IL-2Rα, sCD25) inhibited the anticancer effects of CTLA-4 blockade. In 262 metastatic melanoma patients receiving ipilimumab, baseline serum concentrations of sCD25 represented an independent indicator of overall survival, with high levels predicting resistance to therapy. Altogether, these results unravel a role for IL-2 and IL-2 receptors in the anticancer activity of CTLA-4 blockade. Importantly, our study provides the first immunologically relevant biomarker, namely elevated serum sCD25, that predicts resistance to CTLA-4 blockade in patients with melanoma.</p></abstract><kwd-group><kwd>ipilimumab</kwd><kwd>CTLA-4 blockade</kwd><kwd>IL-2</kwd><kwd>CD122</kwd><kwd>sCD25</kwd><kwd>tumor immunotherapy</kwd><kwd>cancer</kwd></kwd-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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