A Threshold Level of Intratumor CD8+ T-cell PD1 Expression Dictates Therapeutic Response to Anti-PD1.
Identifieur interne : 003255 ( Main/Exploration ); précédent : 003254; suivant : 003256A 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.
Descripteurs français
- KwdFr :
- Adénocarcinome (), Adénocarcinome (immunologie), Animaux, Anticorps monoclonaux (usage thérapeutique), Antigène CD274 (physiologie), Cellules myéloïdes (immunologie), Cellules myéloïdes (métabolisme), Femelle, Immunisation passive, Immunité acquise, Lymphocytes T CD8+ (immunologie), Lymphocytes T CD8+ (métabolisme), Lymphocytes T régulateurs (immunologie), Lymphocytes TIL (immunologie), Lymphocytes TIL (métabolisme), Microenvironnement tumoral (immunologie), Protéines tumorales (biosynthèse), Protéines tumorales (génétique), Protéines tumorales (physiologie), Récepteur-1 de mort cellulaire programmée (biosynthèse), Récepteur-1 de mort cellulaire programmée (génétique), Récepteur-1 de mort cellulaire programmée (physiologie), Régulation de l'expression des gènes tumoraux (immunologie), Régulation négative, Souris, Souris de lignée BALB C, Souris de lignée C57BL, Souris transgéniques, Tumeurs du côlon (), Tumeurs du côlon (immunologie), Tumeurs expérimentales de la mamelle (), Tumeurs expérimentales de la mamelle (immunologie).
- MESH :
- biosynthèse : Protéines tumorales, Récepteur-1 de mort cellulaire programmée.
- génétique : Protéines tumorales, Récepteur-1 de mort cellulaire programmée.
- immunologie : Adénocarcinome, Cellules myéloïdes, Lymphocytes T CD8+, Lymphocytes T régulateurs, Lymphocytes TIL, Microenvironnement tumoral, Régulation de l'expression des gènes tumoraux, Tumeurs du côlon, Tumeurs expérimentales de la mamelle.
- métabolisme : Cellules myéloïdes, Lymphocytes T CD8+, Lymphocytes TIL.
- physiologie : Antigène CD274, Protéines tumorales, Récepteur-1 de mort cellulaire programmée.
- usage thérapeutique : Anticorps monoclonaux.
- Adénocarcinome, Animaux, Femelle, Immunisation passive, Immunité acquise, Régulation négative, Souris, Souris de lignée BALB C, Souris de lignée C57BL, Souris transgéniques, Tumeurs du côlon, Tumeurs expérimentales de la mamelle.
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:
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Center of Clinical Investigations in Biotherapies of Cancer (CICBT), Villejuif, France. Metabolomics and Cell Biology Platforms, Institut de Cancerologie Gustave Roussy, Villejuif</wicri:regionArea><wicri:noRegion>Villejuif</wicri:noRegion><wicri:noRegion>Villejuif</wicri:noRegion></affiliation></author><author><name sortKey="Zitvogel, Laurence" sort="Zitvogel, Laurence" uniqKey="Zitvogel L" first="Laurence" last="Zitvogel">Laurence Zitvogel</name><affiliation wicri:level="1"><nlm: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.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>Villejuif</wicri:noRegion><wicri:noRegion>Villejuif</wicri:noRegion></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 wicri:level="1"><nlm:affiliation>Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. School of Medicine, University of Queensland, Herston, Queensland, Australia. mark.smyth@qimrberghofer.edu.au.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. 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School of Medicine, University of Queensland, Herston, Queensland, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. School of Medicine, University of Queensland, Herston, Queensland</wicri:regionArea><wicri:noRegion>Queensland</wicri:noRegion></affiliation></author><author><name sortKey="Young, Arabella" sort="Young, Arabella" uniqKey="Young A" first="Arabella" last="Young">Arabella Young</name><affiliation wicri:level="1"><nlm:affiliation>Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. School of Medicine, University of Queensland, Herston, Queensland, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. School of Medicine, University of Queensland, Herston, Queensland</wicri:regionArea><wicri:noRegion>Queensland</wicri:noRegion></affiliation></author><author><name sortKey="Jacquelot, Nicolas" sort="Jacquelot, Nicolas" uniqKey="Jacquelot N" first="Nicolas" last="Jacquelot">Nicolas Jacquelot</name><affiliation wicri:level="1"><nlm: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.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>Villejuif</wicri:noRegion><wicri:noRegion>Villejuif</wicri:noRegion></affiliation></author><author><name sortKey="Yamazaki, Takahiro" sort="Yamazaki, Takahiro" uniqKey="Yamazaki T" first="Takahiro" last="Yamazaki">Takahiro Yamazaki</name><affiliation wicri:level="1"><nlm: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.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>Villejuif</wicri:noRegion><wicri:noRegion>Villejuif</wicri:noRegion></affiliation></author><author><name sortKey="Enot, David" sort="Enot, David" uniqKey="Enot D" first="David" last="Enot">David Enot</name><affiliation wicri:level="1"><nlm: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.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>Villejuif</wicri:noRegion><wicri:noRegion>Villejuif</wicri:noRegion></affiliation></author><author><name sortKey="Zitvogel, Laurence" sort="Zitvogel, Laurence" uniqKey="Zitvogel L" first="Laurence" last="Zitvogel">Laurence Zitvogel</name><affiliation wicri:level="1"><nlm: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.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>Villejuif</wicri:noRegion><wicri:noRegion>Villejuif</wicri:noRegion></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 wicri:level="1"><nlm:affiliation>Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. School of Medicine, University of Queensland, Herston, Queensland, Australia. mark.smyth@qimrberghofer.edu.au.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. School of Medicine, University of Queensland, Herston, Queensland</wicri:regionArea><wicri:noRegion>Queensland</wicri:noRegion></affiliation></author></analytic><series><title level="j">Cancer research</title><idno type="eISSN">1538-7445</idno><imprint><date when="2015" type="published">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adaptive Immunity</term><term>Adenocarcinoma (immunology)</term><term>Adenocarcinoma (therapy)</term><term>Animals</term><term>Antibodies, Monoclonal (therapeutic use)</term><term>Antigens, CD274 (physiology)</term><term>CD8-Positive T-Lymphocytes (immunology)</term><term>CD8-Positive T-Lymphocytes (metabolism)</term><term>Colonic Neoplasms (immunology)</term><term>Colonic Neoplasms (therapy)</term><term>Down-Regulation</term><term>Female</term><term>Gene Expression Regulation, Neoplastic (immunology)</term><term>Immunization, Passive</term><term>Lymphocytes, Tumor-Infiltrating (immunology)</term><term>Lymphocytes, Tumor-Infiltrating (metabolism)</term><term>Mammary Neoplasms, Experimental (immunology)</term><term>Mammary Neoplasms, Experimental (therapy)</term><term>Mice</term><term>Mice, Inbred BALB C</term><term>Mice, Inbred C57BL</term><term>Mice, Transgenic</term><term>Myeloid Cells (immunology)</term><term>Myeloid Cells (metabolism)</term><term>Neoplasm Proteins (biosynthesis)</term><term>Neoplasm Proteins (genetics)</term><term>Neoplasm Proteins (physiology)</term><term>Programmed Cell Death 1 Receptor (biosynthesis)</term><term>Programmed Cell Death 1 Receptor (genetics)</term><term>Programmed Cell Death 1 Receptor (physiology)</term><term>T-Lymphocytes, Regulatory (immunology)</term><term>Tumor Microenvironment (immunology)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Adénocarcinome ()</term><term>Adénocarcinome (immunologie)</term><term>Animaux</term><term>Anticorps monoclonaux (usage thérapeutique)</term><term>Antigène CD274 (physiologie)</term><term>Cellules myéloïdes (immunologie)</term><term>Cellules myéloïdes (métabolisme)</term><term>Femelle</term><term>Immunisation passive</term><term>Immunité acquise</term><term>Lymphocytes T CD8+ (immunologie)</term><term>Lymphocytes T CD8+ (métabolisme)</term><term>Lymphocytes T régulateurs (immunologie)</term><term>Lymphocytes TIL (immunologie)</term><term>Lymphocytes TIL (métabolisme)</term><term>Microenvironnement tumoral (immunologie)</term><term>Protéines tumorales (biosynthèse)</term><term>Protéines tumorales (génétique)</term><term>Protéines tumorales (physiologie)</term><term>Récepteur-1 de mort cellulaire programmée (biosynthèse)</term><term>Récepteur-1 de mort cellulaire programmée (génétique)</term><term>Récepteur-1 de mort cellulaire programmée (physiologie)</term><term>Régulation de l'expression des gènes tumoraux (immunologie)</term><term>Régulation négative</term><term>Souris</term><term>Souris de lignée BALB C</term><term>Souris de lignée C57BL</term><term>Souris transgéniques</term><term>Tumeurs du côlon ()</term><term>Tumeurs du côlon (immunologie)</term><term>Tumeurs expérimentales de la mamelle ()</term><term>Tumeurs expérimentales de la mamelle (immunologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="biosynthesis" xml:lang="en"><term>Neoplasm Proteins</term><term>Programmed Cell Death 1 Receptor</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Neoplasm Proteins</term><term>Programmed Cell Death 1 Receptor</term></keywords><keywords scheme="MESH" type="chemical" qualifier="physiology" xml:lang="en"><term>Antigens, CD274</term><term>Neoplasm Proteins</term><term>Programmed Cell Death 1 Receptor</term></keywords><keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Antibodies, Monoclonal</term></keywords><keywords scheme="MESH" qualifier="biosynthèse" xml:lang="fr"><term>Protéines tumorales</term><term>Récepteur-1 de mort cellulaire programmée</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Protéines tumorales</term><term>Récepteur-1 de mort cellulaire programmée</term></keywords><keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>Adénocarcinome</term><term>Cellules myéloïdes</term><term>Lymphocytes T CD8+</term><term>Lymphocytes T régulateurs</term><term>Lymphocytes TIL</term><term>Microenvironnement tumoral</term><term>Régulation de l'expression des gènes tumoraux</term><term>Tumeurs du côlon</term><term>Tumeurs expérimentales de la mamelle</term></keywords><keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>Adenocarcinoma</term><term>CD8-Positive T-Lymphocytes</term><term>Colonic Neoplasms</term><term>Gene Expression Regulation, Neoplastic</term><term>Lymphocytes, Tumor-Infiltrating</term><term>Mammary Neoplasms, Experimental</term><term>Myeloid Cells</term><term>T-Lymphocytes, Regulatory</term><term>Tumor Microenvironment</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>CD8-Positive T-Lymphocytes</term><term>Lymphocytes, Tumor-Infiltrating</term><term>Myeloid Cells</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Cellules myéloïdes</term><term>Lymphocytes T CD8+</term><term>Lymphocytes TIL</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Antigène CD274</term><term>Protéines tumorales</term><term>Récepteur-1 de mort cellulaire programmée</term></keywords><keywords scheme="MESH" qualifier="therapy" xml:lang="en"><term>Adenocarcinoma</term><term>Colonic Neoplasms</term><term>Mammary Neoplasms, Experimental</term></keywords><keywords scheme="MESH" qualifier="usage thérapeutique" xml:lang="fr"><term>Anticorps monoclonaux</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Adaptive Immunity</term><term>Animals</term><term>Down-Regulation</term><term>Female</term><term>Immunization, Passive</term><term>Mice</term><term>Mice, Inbred BALB C</term><term>Mice, Inbred C57BL</term><term>Mice, Transgenic</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Adénocarcinome</term><term>Animaux</term><term>Femelle</term><term>Immunisation passive</term><term>Immunité acquise</term><term>Régulation négative</term><term>Souris</term><term>Souris de lignée BALB C</term><term>Souris de lignée C57BL</term><term>Souris transgéniques</term><term>Tumeurs du côlon</term><term>Tumeurs expérimentales de la mamelle</term></keywords></textClass></profileDesc></teiHeader><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><affiliations><list><country><li>Australie</li><li>France</li></country></list><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></noRegion><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></country><country name="France"><noRegion><name sortKey="Jacquelot, Nicolas" sort="Jacquelot, Nicolas" uniqKey="Jacquelot N" first="Nicolas" last="Jacquelot">Nicolas Jacquelot</name></noRegion><name sortKey="Enot, David" sort="Enot, David" uniqKey="Enot D" first="David" last="Enot">David Enot</name><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></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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