AustralieFrV1, PubMed, Checkpoint, bibRecord, 003027

A Threshold Level of Intratumor CD8+ T-cell PD1 Expression Dictates Therapeutic Response to Anti-PD1.

Identifieur interne : 003027 ( PubMed/Checkpoint ); précédent : 003026; suivant : 003028

A Threshold Level of Intratumor CD8+ T-cell PD1 Expression Dictates Therapeutic Response to Anti-PD1.

Auteurs : Shin Foong Ngiow [Australie] ; Arabella Young [Australie] ; Nicolas Jacquelot [France] ; Takahiro Yamazaki [France] ; David Enot [France] ; Laurence Zitvogel [France] ; Mark J. Smyth [Australie]

Source :

Cancer research [ 1538-7445 ] ; 2015.

RBID : pubmed:26208901

Descripteurs français

English descriptors

KwdEn :
- Adaptive Immunity, Adenocarcinoma (immunology), Adenocarcinoma (therapy), Animals, Antibodies, Monoclonal (therapeutic use), Antigens, CD274 (physiology), CD8-Positive T-Lymphocytes (immunology), CD8-Positive T-Lymphocytes (metabolism), Colonic Neoplasms (immunology), Colonic Neoplasms (therapy), Down-Regulation, Female, Gene Expression Regulation, Neoplastic (immunology), Immunization, Passive, Lymphocytes, Tumor-Infiltrating (immunology), Lymphocytes, Tumor-Infiltrating (metabolism), Mammary Neoplasms, Experimental (immunology), Mammary Neoplasms, Experimental (therapy), Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, Myeloid Cells (immunology), Myeloid Cells (metabolism), Neoplasm Proteins (biosynthesis), Neoplasm Proteins (genetics), Neoplasm Proteins (physiology), Programmed Cell Death 1 Receptor (biosynthesis), Programmed Cell Death 1 Receptor (genetics), Programmed Cell Death 1 Receptor (physiology), T-Lymphocytes, Regulatory (immunology), Tumor Microenvironment (immunology).
MESH :
- chemical , biosynthesis : Neoplasm Proteins, Programmed Cell Death 1 Receptor.
- chemical , genetics : Neoplasm Proteins, Programmed Cell Death 1 Receptor.
- chemical , physiology : Antigens, CD274, Neoplasm Proteins, Programmed Cell Death 1 Receptor.
- chemical , therapeutic use : Antibodies, Monoclonal.
- immunology : Adenocarcinoma, CD8-Positive T-Lymphocytes, Colonic Neoplasms, Gene Expression Regulation, Neoplastic, Lymphocytes, Tumor-Infiltrating, Mammary Neoplasms, Experimental, Myeloid Cells, T-Lymphocytes, Regulatory, Tumor Microenvironment.
- metabolism : CD8-Positive T-Lymphocytes, Lymphocytes, Tumor-Infiltrating, Myeloid Cells.
- therapy : Adenocarcinoma, Colonic Neoplasms, Mammary Neoplasms, Experimental.
- Adaptive Immunity, Animals, Down-Regulation, Female, Immunization, Passive, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic.

Abstract

Despite successes, thus far, a significant proportion of the patients treated with anti-PD1 antibodies have failed to respond. We use mouse tumor models of anti-PD1 sensitivity and resistance and flow cytometry to assess tumor-infiltrating immune cells immediately after therapy. We demonstrate that the expression levels of T-cell PD1 (PD1(lo)), myeloid, and T-cell PDL1 (PDL1(hi)) in the tumor microenvironment inversely correlate and dictate the efficacy of anti-PD1 mAb and function of intratumor CD8(+) T cells. In sensitive tumors, we reveal a threshold for PD1 downregulation on tumor-infiltrating CD8(+) T cells below which the release of adaptive immune resistance is achieved. In contrast, PD1(hi) T cells in resistant tumors fail to be rescued by anti-PD1 therapy and remain dysfunctional unless intratumor PDL1(lo) immune cells are targeted. Intratumor Tregs are partly responsible for the development of anti-PD1-resistant tumors and PD1(hi) CD8(+) T cells. Our analyses provide a framework to interrogate intratumor CD8(+) T-cell PD1 and immune PDL1 levels and response in human cancer.

DOI: 10.1158/0008-5472.CAN-15-1082
PubMed: 26208901

Affiliations:

Australie, France

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Le document en format XML

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<front><div type="abstract" xml:lang="en">Despite successes, thus far, a significant proportion of the patients treated with anti-PD1 antibodies have failed to respond. We use mouse tumor models of anti-PD1 sensitivity and resistance and flow cytometry to assess tumor-infiltrating immune cells immediately after therapy. We demonstrate that the expression levels of T-cell PD1 (PD1(lo)), myeloid, and T-cell PDL1 (PDL1(hi)) in the tumor microenvironment inversely correlate and dictate the efficacy of anti-PD1 mAb and function of intratumor CD8(+) T cells. In sensitive tumors, we reveal a threshold for PD1 downregulation on tumor-infiltrating CD8(+) T cells below which the release of adaptive immune resistance is achieved. In contrast, PD1(hi) T cells in resistant tumors fail to be rescued by anti-PD1 therapy and remain dysfunctional unless intratumor PDL1(lo) immune cells are targeted. Intratumor Tregs are partly responsible for the development of anti-PD1-resistant tumors and PD1(hi) CD8(+) T cells. Our analyses provide a framework to interrogate intratumor CD8(+) T-cell PD1 and immune PDL1 levels and response in human cancer.</div>
</front>
</TEI>
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<DateCreated><Year>2015</Year>
<Month>09</Month>
<Day>16</Day>
</DateCreated>
<DateCompleted><Year>2016</Year>
<Month>01</Month>
<Day>04</Day>
</DateCompleted>
<DateRevised><Year>2017</Year>
<Month>11</Month>
<Day>16</Day>
</DateRevised>
<Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1538-7445</ISSN>
<JournalIssue CitedMedium="Internet"><Volume>75</Volume>
<Issue>18</Issue>
<PubDate><Year>2015</Year>
<Month>Sep</Month>
<Day>15</Day>
</PubDate>
</JournalIssue>
<Title>Cancer research</Title>
<ISOAbbreviation>Cancer Res.</ISOAbbreviation>
</Journal>
<ArticleTitle>A Threshold Level of Intratumor CD8+ T-cell PD1 Expression Dictates Therapeutic Response to Anti-PD1.</ArticleTitle>
<Pagination><MedlinePgn>3800-11</MedlinePgn>
</Pagination>
<ELocationID EIdType="doi" ValidYN="Y">10.1158/0008-5472.CAN-15-1082</ELocationID>
<Abstract><AbstractText>Despite successes, thus far, a significant proportion of the patients treated with anti-PD1 antibodies have failed to respond. We use mouse tumor models of anti-PD1 sensitivity and resistance and flow cytometry to assess tumor-infiltrating immune cells immediately after therapy. We demonstrate that the expression levels of T-cell PD1 (PD1(lo)), myeloid, and T-cell PDL1 (PDL1(hi)) in the tumor microenvironment inversely correlate and dictate the efficacy of anti-PD1 mAb and function of intratumor CD8(+) T cells. In sensitive tumors, we reveal a threshold for PD1 downregulation on tumor-infiltrating CD8(+) T cells below which the release of adaptive immune resistance is achieved. In contrast, PD1(hi) T cells in resistant tumors fail to be rescued by anti-PD1 therapy and remain dysfunctional unless intratumor PDL1(lo) immune cells are targeted. Intratumor Tregs are partly responsible for the development of anti-PD1-resistant tumors and PD1(hi) CD8(+) T cells. Our analyses provide a framework to interrogate intratumor CD8(+) T-cell PD1 and immune PDL1 levels and response in human cancer.</AbstractText>
<CopyrightInformation>©2015 American Association for Cancer Research.</CopyrightInformation>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Ngiow</LastName>
<ForeName>Shin Foong</ForeName>
<Initials>SF</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>Young</LastName>
<ForeName>Arabella</ForeName>
<Initials>A</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>
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<Author ValidYN="Y"><LastName>Jacquelot</LastName>
<ForeName>Nicolas</ForeName>
<Initials>N</Initials>
<AffiliationInfo><Affiliation>INSERM U1015, Villejuif, France. Institut de Cancérologie Gustave Roussy, Villejuif, France. Equipe labellisée Ligue contre le Cancer, University of Paris Sud XI, Villejuif, France. Center of Clinical Investigations in Biotherapies of Cancer (CICBT), Villejuif, France.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Yamazaki</LastName>
<ForeName>Takahiro</ForeName>
<Initials>T</Initials>
<AffiliationInfo><Affiliation>INSERM U1015, Villejuif, France. Institut de Cancérologie Gustave Roussy, Villejuif, France. Equipe labellisée Ligue contre le Cancer, University of Paris Sud XI, Villejuif, France. Center of Clinical Investigations in Biotherapies of Cancer (CICBT), Villejuif, France.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Enot</LastName>
<ForeName>David</ForeName>
<Initials>D</Initials>
<AffiliationInfo><Affiliation>INSERM U1015, Villejuif, France. Institut de Cancérologie Gustave Roussy, Villejuif, France. Equipe labellisée Ligue contre le Cancer, University of Paris Sud XI, Villejuif, France. Center of Clinical Investigations in Biotherapies of Cancer (CICBT), Villejuif, France. Metabolomics and Cell Biology Platforms, Institut de Cancerologie Gustave Roussy, Villejuif, France.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Zitvogel</LastName>
<ForeName>Laurence</ForeName>
<Initials>L</Initials>
<AffiliationInfo><Affiliation>INSERM U1015, Villejuif, France. Institut de Cancérologie Gustave Roussy, Villejuif, France. Equipe labellisée Ligue contre le Cancer, University of Paris Sud XI, Villejuif, France. Center of Clinical Investigations in Biotherapies of Cancer (CICBT), Villejuif, France.</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>2015</Year>
<Month>07</Month>
<Day>24</Day>
</ArticleDate>
</Article>
<MedlineJournalInfo><Country>United States</Country>
<MedlineTA>Cancer Res</MedlineTA>
<NlmUniqueID>2984705R</NlmUniqueID>
<ISSNLinking>0008-5472</ISSNLinking>
</MedlineJournalInfo>
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<NameOfSubstance UI="D000911">Antibodies, Monoclonal</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D060890">Antigens, CD274</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="C498919">Cd274 protein, mouse</NameOfSubstance>
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<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D009363">Neoplasm Proteins</NameOfSubstance>
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<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="C491383">Pdcd1 protein, mouse</NameOfSubstance>
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<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D061026">Programmed Cell Death 1 Receptor</NameOfSubstance>
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<CitationSubset>IM</CitationSubset>
<MeshHeadingList><MeshHeading><DescriptorName UI="D056704" MajorTopicYN="N">Adaptive Immunity</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D000230" MajorTopicYN="N">Adenocarcinoma</DescriptorName>
<QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName>
<QualifierName UI="Q000628" MajorTopicYN="Y">therapy</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D000911" MajorTopicYN="N">Antibodies, Monoclonal</DescriptorName>
<QualifierName UI="Q000627" MajorTopicYN="Y">therapeutic use</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D060890" MajorTopicYN="N">Antigens, CD274</DescriptorName>
<QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D018414" MajorTopicYN="N">CD8-Positive T-Lymphocytes</DescriptorName>
<QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D003110" MajorTopicYN="N">Colonic Neoplasms</DescriptorName>
<QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName>
<QualifierName UI="Q000628" MajorTopicYN="Y">therapy</QualifierName>
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<MeshHeading><DescriptorName UI="D015536" MajorTopicYN="N">Down-Regulation</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D015972" MajorTopicYN="N">Gene Expression Regulation, Neoplastic</DescriptorName>
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<QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName>
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<QualifierName UI="Q000628" MajorTopicYN="Y">therapy</QualifierName>
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<MeshHeading><DescriptorName UI="D008810" MajorTopicYN="N">Mice, Inbred C57BL</DescriptorName>
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<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
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<QualifierName UI="Q000502" MajorTopicYN="Y">physiology</QualifierName>
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<MeshHeading><DescriptorName UI="D050378" MajorTopicYN="N">T-Lymphocytes, Regulatory</DescriptorName>
<QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName>
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<QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName>
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<PubmedData><History><PubMedPubDate PubStatus="received"><Year>2015</Year>
<Month>04</Month>
<Day>22</Day>
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<PubMedPubDate PubStatus="accepted"><Year>2015</Year>
<Month>07</Month>
<Day>02</Day>
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<ArticleId IdType="doi">10.1158/0008-5472.CAN-15-1082</ArticleId>
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<affiliations><list><country><li>Australie</li>
<li>France</li>
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<tree><country name="Australie"><noRegion><name sortKey="Ngiow, Shin Foong" sort="Ngiow, Shin Foong" uniqKey="Ngiow S" first="Shin Foong" last="Ngiow">Shin Foong Ngiow</name>
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<name sortKey="Smyth, Mark J" sort="Smyth, Mark J" uniqKey="Smyth M" first="Mark J" last="Smyth">Mark J. Smyth</name>
<name sortKey="Young, Arabella" sort="Young, Arabella" uniqKey="Young A" first="Arabella" last="Young">Arabella Young</name>
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<country name="France"><noRegion><name sortKey="Jacquelot, Nicolas" sort="Jacquelot, Nicolas" uniqKey="Jacquelot N" first="Nicolas" last="Jacquelot">Nicolas Jacquelot</name>
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<name sortKey="Yamazaki, Takahiro" sort="Yamazaki, Takahiro" uniqKey="Yamazaki T" first="Takahiro" last="Yamazaki">Takahiro Yamazaki</name>
<name sortKey="Zitvogel, Laurence" sort="Zitvogel, Laurence" uniqKey="Zitvogel L" first="Laurence" last="Zitvogel">Laurence Zitvogel</name>
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</tree>
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A Threshold Level of Intratumor CD8+ T-cell PD1 Expression Dictates Therapeutic Response to Anti-PD1.

A Threshold Level of Intratumor CD8+ T-cell PD1 Expression Dictates Therapeutic Response to Anti-PD1.

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