Adenosine Receptor 2A Blockade Increases the Efficacy of Anti-PD-1 through Enhanced Antitumor T-cell Responses.
Identifieur interne : 000590 ( PubMed/Checkpoint ); précédent : 000589; suivant : 000591Adenosine Receptor 2A Blockade Increases the Efficacy of Anti-PD-1 through Enhanced Antitumor T-cell Responses.
Auteurs : Paul A. Beavis [Australie] ; Nicole Milenkovski [Australie] ; Melissa A. Henderson [Australie] ; Liza B. John [Australie] ; Bertrand Allard [Canada] ; Sherene Loi [Australie] ; Michael H. Kershaw [Australie] ; John Stagg [Canada] ; Phillip K. Darcy [Australie]Source :
- Cancer immunology research [ 2326-6074 ] ; 2015.
English descriptors
- KwdEn :
- Adenosine A2 Receptor Antagonists (pharmacology), Adenosine-5'-(N-ethylcarboxamide) (pharmacology), Animals, Antibodies, Monoclonal (pharmacology), CD8-Positive T-Lymphocytes (drug effects), CD8-Positive T-Lymphocytes (immunology), Cell Line, Tumor, Humans, Interferon-gamma (immunology), Leukocytes, Mononuclear (drug effects), Leukocytes, Mononuclear (immunology), Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, Programmed Cell Death 1 Receptor (immunology), Pyrimidines (pharmacology), Triazoles (pharmacology).
- MESH :
- chemical , immunology : Interferon-gamma, Programmed Cell Death 1 Receptor.
- chemical , pharmacology : Adenosine A2 Receptor Antagonists, Adenosine-5'-(N-ethylcarboxamide), Antibodies, Monoclonal, Pyrimidines, Triazoles.
- drug effects : CD8-Positive T-Lymphocytes, Leukocytes, Mononuclear.
- immunology : CD8-Positive T-Lymphocytes, Leukocytes, Mononuclear.
- Animals, Cell Line, Tumor, Humans, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic.
Abstract
Immunotherapy is rapidly emerging as a cancer treatment with high potential. Recent clinical trials with anti-CTLA-4 and anti-PD-1/PD-L1 antibodies (mAbs) suggest that targeting multiple immunosuppressive pathways may significantly improve patient survival. The generation of adenosine by CD73 also suppresses antitumor immune responses through the activation of A2A receptors on T cells and natural killer (NK) cells. We sought to determine whether blockade of A2A receptors could enhance the efficacy of anti-PD-1 mAb. The expression of CD73 by tumor cells limited the efficacy of anti-PD-1 mAb in two tumor models, and this was alleviated with concomitant treatment with an A2A adenosine receptor antagonist. The blockade of PD-1 enhanced A2A receptor expression on tumor-infiltrating CD8(+) T cells, making them more susceptible to A2A-mediated suppression. Thus, dual blockade of PD-1 and A2A significantly enhanced the expression of IFNγ and Granzyme B by tumor-infiltrating CD8(+) T cells and, accordingly, increased growth inhibition of CD73(+) tumors and survival of mice. The results of our study indicate that CD73 expression may constitute a potential biomarker for the efficacy of anti-PD-1 mAb in patients with cancer and that the efficacy of anti-PD-1 mAb can be significantly enhanced by A2A antagonists. We have therefore revealed a potentially novel biomarker for the efficacy of anti-PD-1 that warrants further investigation in patients. Because our studies used SYN-115, a drug that has already undergone phase IIb testing in Parkinson disease, our findings have immediate translational relevance for patients with cancer.
DOI: 10.1158/2326-6066.CIR-14-0211
PubMed: 25672397
Affiliations:
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Department of Immunology, Monash University, Clayton, Victoria, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. Department of Pathology, University of Melbourne, Parkville, Victoria, Australia. Department of Immunology, Monash University, Clayton, Victoria</wicri:regionArea><wicri:noRegion>Victoria</wicri:noRegion></affiliation></author><author><name sortKey="Stagg, John" sort="Stagg, John" uniqKey="Stagg J" first="John" last="Stagg">John Stagg</name><affiliation wicri:level="1"><nlm:affiliation>Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Faculté de Pharmacie et Institut du Cancer de Montréal, Montréal, Québec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Faculté de Pharmacie et Institut du Cancer de Montréal, Montréal, Québec</wicri:regionArea><wicri:noRegion>Québec</wicri:noRegion></affiliation></author><author><name sortKey="Darcy, Phillip K" sort="Darcy, Phillip K" uniqKey="Darcy P" first="Phillip K" last="Darcy">Phillip K. 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Beavis</name><affiliation wicri:level="1"><nlm:affiliation>Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. phil.darcy@petermac.org paula.beavis@petermac.org.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria</wicri:regionArea><wicri:noRegion>Victoria</wicri:noRegion></affiliation></author><author><name sortKey="Milenkovski, Nicole" sort="Milenkovski, Nicole" uniqKey="Milenkovski N" first="Nicole" last="Milenkovski">Nicole Milenkovski</name><affiliation wicri:level="1"><nlm:affiliation>Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria</wicri:regionArea><wicri:noRegion>Victoria</wicri:noRegion></affiliation></author><author><name sortKey="Henderson, Melissa A" sort="Henderson, Melissa A" uniqKey="Henderson M" first="Melissa A" last="Henderson">Melissa A. Henderson</name><affiliation wicri:level="1"><nlm:affiliation>Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria</wicri:regionArea><wicri:noRegion>Victoria</wicri:noRegion></affiliation></author><author><name sortKey="John, Liza B" sort="John, Liza B" uniqKey="John L" first="Liza B" last="John">Liza B. John</name><affiliation wicri:level="1"><nlm:affiliation>Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria</wicri:regionArea><wicri:noRegion>Victoria</wicri:noRegion></affiliation></author><author><name sortKey="Allard, Bertrand" sort="Allard, Bertrand" uniqKey="Allard B" first="Bertrand" last="Allard">Bertrand Allard</name><affiliation wicri:level="1"><nlm:affiliation>Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Faculté de Pharmacie et Institut du Cancer de Montréal, Montréal, Québec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Faculté de Pharmacie et Institut du Cancer de Montréal, Montréal, Québec</wicri:regionArea><wicri:noRegion>Québec</wicri:noRegion></affiliation></author><author><name sortKey="Loi, Sherene" sort="Loi, Sherene" uniqKey="Loi S" first="Sherene" last="Loi">Sherene Loi</name><affiliation wicri:level="1"><nlm:affiliation>Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria</wicri:regionArea><wicri:noRegion>Victoria</wicri:noRegion></affiliation></author><author><name sortKey="Kershaw, Michael H" sort="Kershaw, Michael H" uniqKey="Kershaw M" first="Michael H" last="Kershaw">Michael H. Kershaw</name><affiliation wicri:level="1"><nlm:affiliation>Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. Department of Pathology, University of Melbourne, Parkville, Victoria, Australia. Department of Immunology, Monash University, Clayton, Victoria, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. Department of Pathology, University of Melbourne, Parkville, Victoria, Australia. Department of Immunology, Monash University, Clayton, Victoria</wicri:regionArea><wicri:noRegion>Victoria</wicri:noRegion></affiliation></author><author><name sortKey="Stagg, John" sort="Stagg, John" uniqKey="Stagg J" first="John" last="Stagg">John Stagg</name><affiliation wicri:level="1"><nlm:affiliation>Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Faculté de Pharmacie et Institut du Cancer de Montréal, Montréal, Québec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Faculté de Pharmacie et Institut du Cancer de Montréal, Montréal, Québec</wicri:regionArea><wicri:noRegion>Québec</wicri:noRegion></affiliation></author><author><name sortKey="Darcy, Phillip K" sort="Darcy, Phillip K" uniqKey="Darcy P" first="Phillip K" last="Darcy">Phillip K. Darcy</name><affiliation wicri:level="1"><nlm:affiliation>Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. Department of Pathology, University of Melbourne, Parkville, Victoria, Australia. Department of Immunology, Monash University, Clayton, Victoria, Australia. phil.darcy@petermac.org paula.beavis@petermac.org.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. Department of Pathology, University of Melbourne, Parkville, Victoria, Australia. Department of Immunology, Monash University, Clayton, Victoria</wicri:regionArea><wicri:noRegion>Victoria</wicri:noRegion></affiliation></author></analytic><series><title level="j">Cancer immunology research</title><idno type="eISSN">2326-6074</idno><imprint><date when="2015" type="published">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adenosine A2 Receptor Antagonists (pharmacology)</term><term>Adenosine-5'-(N-ethylcarboxamide) (pharmacology)</term><term>Animals</term><term>Antibodies, Monoclonal (pharmacology)</term><term>CD8-Positive T-Lymphocytes (drug effects)</term><term>CD8-Positive T-Lymphocytes (immunology)</term><term>Cell Line, Tumor</term><term>Humans</term><term>Interferon-gamma (immunology)</term><term>Leukocytes, Mononuclear (drug effects)</term><term>Leukocytes, Mononuclear (immunology)</term><term>Mice, Inbred BALB C</term><term>Mice, Inbred C57BL</term><term>Mice, Transgenic</term><term>Programmed Cell Death 1 Receptor (immunology)</term><term>Pyrimidines (pharmacology)</term><term>Triazoles (pharmacology)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="immunology" xml:lang="en"><term>Interferon-gamma</term><term>Programmed Cell Death 1 Receptor</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Adenosine A2 Receptor Antagonists</term><term>Adenosine-5'-(N-ethylcarboxamide)</term><term>Antibodies, Monoclonal</term><term>Pyrimidines</term><term>Triazoles</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>CD8-Positive T-Lymphocytes</term><term>Leukocytes, Mononuclear</term></keywords><keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>CD8-Positive T-Lymphocytes</term><term>Leukocytes, Mononuclear</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Cell Line, Tumor</term><term>Humans</term><term>Mice, Inbred BALB C</term><term>Mice, Inbred C57BL</term><term>Mice, Transgenic</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Immunotherapy is rapidly emerging as a cancer treatment with high potential. Recent clinical trials with anti-CTLA-4 and anti-PD-1/PD-L1 antibodies (mAbs) suggest that targeting multiple immunosuppressive pathways may significantly improve patient survival. The generation of adenosine by CD73 also suppresses antitumor immune responses through the activation of A2A receptors on T cells and natural killer (NK) cells. We sought to determine whether blockade of A2A receptors could enhance the efficacy of anti-PD-1 mAb. The expression of CD73 by tumor cells limited the efficacy of anti-PD-1 mAb in two tumor models, and this was alleviated with concomitant treatment with an A2A adenosine receptor antagonist. The blockade of PD-1 enhanced A2A receptor expression on tumor-infiltrating CD8(+) T cells, making them more susceptible to A2A-mediated suppression. Thus, dual blockade of PD-1 and A2A significantly enhanced the expression of IFNγ and Granzyme B by tumor-infiltrating CD8(+) T cells and, accordingly, increased growth inhibition of CD73(+) tumors and survival of mice. The results of our study indicate that CD73 expression may constitute a potential biomarker for the efficacy of anti-PD-1 mAb in patients with cancer and that the efficacy of anti-PD-1 mAb can be significantly enhanced by A2A antagonists. We have therefore revealed a potentially novel biomarker for the efficacy of anti-PD-1 that warrants further investigation in patients. Because our studies used SYN-115, a drug that has already undergone phase IIb testing in Parkinson disease, our findings have immediate translational relevance for patients with cancer.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">25672397</PMID><DateCreated><Year>2015</Year><Month>05</Month><Day>05</Day></DateCreated><DateCompleted><Year>2016</Year><Month>02</Month><Day>08</Day></DateCompleted><DateRevised><Year>2015</Year><Month>05</Month><Day>05</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">2326-6074</ISSN><JournalIssue CitedMedium="Internet"><Volume>3</Volume><Issue>5</Issue><PubDate><Year>2015</Year><Month>May</Month></PubDate></JournalIssue><Title>Cancer immunology research</Title><ISOAbbreviation>Cancer Immunol Res</ISOAbbreviation></Journal><ArticleTitle>Adenosine Receptor 2A Blockade Increases the Efficacy of Anti-PD-1 through Enhanced Antitumor T-cell Responses.</ArticleTitle><Pagination><MedlinePgn>506-17</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1158/2326-6066.CIR-14-0211</ELocationID><Abstract><AbstractText>Immunotherapy is rapidly emerging as a cancer treatment with high potential. Recent clinical trials with anti-CTLA-4 and anti-PD-1/PD-L1 antibodies (mAbs) suggest that targeting multiple immunosuppressive pathways may significantly improve patient survival. The generation of adenosine by CD73 also suppresses antitumor immune responses through the activation of A2A receptors on T cells and natural killer (NK) cells. We sought to determine whether blockade of A2A receptors could enhance the efficacy of anti-PD-1 mAb. The expression of CD73 by tumor cells limited the efficacy of anti-PD-1 mAb in two tumor models, and this was alleviated with concomitant treatment with an A2A adenosine receptor antagonist. The blockade of PD-1 enhanced A2A receptor expression on tumor-infiltrating CD8(+) T cells, making them more susceptible to A2A-mediated suppression. Thus, dual blockade of PD-1 and A2A significantly enhanced the expression of IFNγ and Granzyme B by tumor-infiltrating CD8(+) T cells and, accordingly, increased growth inhibition of CD73(+) tumors and survival of mice. The results of our study indicate that CD73 expression may constitute a potential biomarker for the efficacy of anti-PD-1 mAb in patients with cancer and that the efficacy of anti-PD-1 mAb can be significantly enhanced by A2A antagonists. We have therefore revealed a potentially novel biomarker for the efficacy of anti-PD-1 that warrants further investigation in patients. Because our studies used SYN-115, a drug that has already undergone phase IIb testing in Parkinson disease, our findings have immediate translational relevance for patients with cancer.</AbstractText><CopyrightInformation>©2015 American Association for Cancer Research.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Beavis</LastName><ForeName>Paul A</ForeName><Initials>PA</Initials><AffiliationInfo><Affiliation>Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. phil.darcy@petermac.org paula.beavis@petermac.org.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Milenkovski</LastName><ForeName>Nicole</ForeName><Initials>N</Initials><AffiliationInfo><Affiliation>Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Henderson</LastName><ForeName>Melissa A</ForeName><Initials>MA</Initials><AffiliationInfo><Affiliation>Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>John</LastName><ForeName>Liza B</ForeName><Initials>LB</Initials><AffiliationInfo><Affiliation>Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Allard</LastName><ForeName>Bertrand</ForeName><Initials>B</Initials><AffiliationInfo><Affiliation>Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Faculté de Pharmacie et Institut du Cancer de Montréal, Montréal, Québec, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Loi</LastName><ForeName>Sherene</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kershaw</LastName><ForeName>Michael H</ForeName><Initials>MH</Initials><AffiliationInfo><Affiliation>Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. Department of Pathology, University of Melbourne, Parkville, Victoria, Australia. Department of Immunology, Monash University, Clayton, Victoria, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Stagg</LastName><ForeName>John</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Faculté de Pharmacie et Institut du Cancer de Montréal, Montréal, Québec, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Darcy</LastName><ForeName>Phillip K</ForeName><Initials>PK</Initials><AffiliationInfo><Affiliation>Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. Department of Pathology, University of Melbourne, Parkville, Victoria, Australia. Department of Immunology, Monash University, Clayton, Victoria, Australia. phil.darcy@petermac.org paula.beavis@petermac.org.</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>2015</Year><Month>02</Month><Day>11</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Cancer Immunol Res</MedlineTA><NlmUniqueID>101614637</NlmUniqueID><ISSNLinking>2326-6066</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C098657">5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D058917">Adenosine A2 Receptor Antagonists</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000911">Antibodies, Monoclonal</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C491383">Pdcd1 protein, mouse</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D061026">Programmed Cell Death 1 Receptor</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D011743">Pyrimidines</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D014230">Triazoles</NameOfSubstance></Chemical><Chemical><RegistryNumber>35920-39-9</RegistryNumber><NameOfSubstance UI="D019830">Adenosine-5'-(N-ethylcarboxamide)</NameOfSubstance></Chemical><Chemical><RegistryNumber>82115-62-6</RegistryNumber><NameOfSubstance UI="D007371">Interferon-gamma</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D058917" MajorTopicYN="N">Adenosine A2 Receptor Antagonists</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D019830" MajorTopicYN="N">Adenosine-5'-(N-ethylcarboxamide)</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000911" MajorTopicYN="N">Antibodies, Monoclonal</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D018414" MajorTopicYN="N">CD8-Positive T-Lymphocytes</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D045744" MajorTopicYN="N">Cell Line, Tumor</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D007371" MajorTopicYN="N">Interferon-gamma</DescriptorName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D007963" MajorTopicYN="N">Leukocytes, Mononuclear</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008807" MajorTopicYN="N">Mice, Inbred BALB C</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008810" MajorTopicYN="N">Mice, Inbred C57BL</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008822" MajorTopicYN="N">Mice, Transgenic</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D061026" MajorTopicYN="N">Programmed Cell Death 1 Receptor</DescriptorName><QualifierName UI="Q000276" MajorTopicYN="Y">immunology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D011743" MajorTopicYN="N">Pyrimidines</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D014230" MajorTopicYN="N">Triazoles</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2014</Year><Month>11</Month><Day>11</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2015</Year><Month>02</Month><Day>02</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2015</Year><Month>2</Month><Day>13</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2015</Year><Month>2</Month><Day>13</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2016</Year><Month>2</Month><Day>9</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">25672397</ArticleId><ArticleId IdType="pii">2326-6066.CIR-14-0211</ArticleId><ArticleId IdType="doi">10.1158/2326-6066.CIR-14-0211</ArticleId></ArticleIdList></PubmedData></pubmed><affiliations><list><country><li>Australie</li><li>Canada</li></country></list><tree><country name="Australie"><noRegion><name sortKey="Beavis, Paul A" sort="Beavis, Paul A" uniqKey="Beavis P" first="Paul A" last="Beavis">Paul A. Beavis</name></noRegion><name sortKey="Darcy, Phillip K" sort="Darcy, Phillip K" uniqKey="Darcy P" first="Phillip K" last="Darcy">Phillip K. Darcy</name><name sortKey="Henderson, Melissa A" sort="Henderson, Melissa A" uniqKey="Henderson M" first="Melissa A" last="Henderson">Melissa A. Henderson</name><name sortKey="John, Liza B" sort="John, Liza B" uniqKey="John L" first="Liza B" last="John">Liza B. John</name><name sortKey="Kershaw, Michael H" sort="Kershaw, Michael H" uniqKey="Kershaw M" first="Michael H" last="Kershaw">Michael H. Kershaw</name><name sortKey="Loi, Sherene" sort="Loi, Sherene" uniqKey="Loi S" first="Sherene" last="Loi">Sherene Loi</name><name sortKey="Milenkovski, Nicole" sort="Milenkovski, Nicole" uniqKey="Milenkovski N" first="Nicole" last="Milenkovski">Nicole Milenkovski</name></country><country name="Canada"><noRegion><name sortKey="Allard, Bertrand" sort="Allard, Bertrand" uniqKey="Allard B" first="Bertrand" last="Allard">Bertrand Allard</name></noRegion><name sortKey="Stagg, John" sort="Stagg, John" uniqKey="Stagg J" first="John" last="Stagg">John Stagg</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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