Targeting TMEM176B Enhances Antitumor Immunity and Augments the Efficacy of Immune Checkpoint Blockers by Unleashing Inflammasome Activation
Identifieur interne : 000615 ( Ncbi/Merge ); précédent : 000614; suivant : 000616Targeting TMEM176B Enhances Antitumor Immunity and Augments the Efficacy of Immune Checkpoint Blockers by Unleashing Inflammasome Activation
Auteurs : Mercedes Segovia [Uruguay] ; Sofia Russo [Uruguay] ; Mathias Jeldres [Uruguay] ; Yamil D. Mahmoud [Argentine] ; Valentina Perez [Uruguay] ; Maite Duhalde [Uruguay] ; Pierre Charnet [France] ; Matthieu Rousset [France] ; Sabina Victoria [Uruguay] ; Florencia Veigas [Argentine] ; Cédric Louvet [France] ; Bernard Vanhove [France] ; R. Andrés Floto [Royaume-Uni] ; Ignacio Anegon [France] ; Maria Cristina Cuturi [France] ; M. Romina Girotti [Argentine] ; Gabriel A. Rabinovich [Argentine] ; Marcelo Hill [Uruguay]Source :
- Cancer Cell [ 1535-6108 ] ; 2019.
Abstract
Although immune checkpoint blockers have yielded significant clinical benefits in patients with different malignancies, the efficacy of these therapies is still limited. Here, we show that disruption of transmembrane protein 176B (TMEM176B) contributes to CD8+ T cell-mediated tumor growth inhibition by unleashing inflammasome activation. Lack of
Url:
DOI: 10.1016/j.ccell.2019.04.003
PubMed: 31085177
PubMed Central: 6521897
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Mahmoud</name><affiliation wicri:level="1"><nlm:aff id="aff3">Laboratories of Immunopathology and Translational Immuno-Oncology, Institute of Biology and Experimental Medicine (IBYME), National Council of Scientific and Technical Investigations (CONICET), C1428 Buenos Aires, Argentina</nlm:aff><country xml:lang="fr">Argentine</country><wicri:regionArea>Laboratories of Immunopathology and Translational Immuno-Oncology, Institute of Biology and Experimental Medicine (IBYME), National Council of Scientific and Technical Investigations (CONICET), C1428 Buenos Aires</wicri:regionArea><wicri:noRegion>C1428 Buenos Aires</wicri:noRegion></affiliation></author><author><name sortKey="Perez, Valentina" sort="Perez, Valentina" uniqKey="Perez V" first="Valentina" last="Perez">Valentina Perez</name><affiliation wicri:level="1"><nlm:aff id="aff1">Laboratory of Immunoregulation and Inflammation, Institut Pasteur de Montevideo, 11400 Montevideo, Uruguay</nlm:aff><country xml:lang="fr">Uruguay</country><wicri:regionArea>Laboratory of Immunoregulation and Inflammation, Institut Pasteur de Montevideo, 11400 Montevideo</wicri:regionArea><wicri:noRegion>11400 Montevideo</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2">Immunobiology Department, Faculty of Medicine, University of the Republic, 11800 Montevideo, Uruguay</nlm:aff><country xml:lang="fr">Uruguay</country><wicri:regionArea>Immunobiology Department, Faculty of Medicine, University of the Republic, 11800 Montevideo</wicri:regionArea><wicri:noRegion>11800 Montevideo</wicri:noRegion></affiliation></author><author><name sortKey="Duhalde, Maite" sort="Duhalde, Maite" uniqKey="Duhalde M" first="Maite" last="Duhalde">Maite Duhalde</name><affiliation wicri:level="1"><nlm:aff id="aff1">Laboratory of Immunoregulation and Inflammation, Institut Pasteur de Montevideo, 11400 Montevideo, Uruguay</nlm:aff><country xml:lang="fr">Uruguay</country><wicri:regionArea>Laboratory of Immunoregulation and Inflammation, Institut Pasteur de Montevideo, 11400 Montevideo</wicri:regionArea><wicri:noRegion>11400 Montevideo</wicri:noRegion></affiliation></author><author><name sortKey="Charnet, Pierre" sort="Charnet, Pierre" uniqKey="Charnet P" first="Pierre" last="Charnet">Pierre Charnet</name><affiliation wicri:level="3"><nlm:aff id="aff4">Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS ENSCM, Université de Montpellier, 34093 Montpellier, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS ENSCM, Université de Montpellier, 34093 Montpellier</wicri:regionArea><placeName><region type="region" nuts="2">Occitanie (région administrative)</region><region type="old region" nuts="2">Languedoc-Roussillon</region><settlement type="city">Montpellier</settlement></placeName></affiliation></author><author><name sortKey="Rousset, Matthieu" sort="Rousset, Matthieu" uniqKey="Rousset M" first="Matthieu" last="Rousset">Matthieu Rousset</name><affiliation wicri:level="3"><nlm:aff id="aff4">Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS ENSCM, Université de Montpellier, 34093 Montpellier, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS ENSCM, Université de Montpellier, 34093 Montpellier</wicri:regionArea><placeName><region type="region" nuts="2">Occitanie (région administrative)</region><region type="old region" nuts="2">Languedoc-Roussillon</region><settlement type="city">Montpellier</settlement></placeName></affiliation></author><author><name sortKey="Victoria, Sabina" sort="Victoria, Sabina" uniqKey="Victoria S" first="Sabina" last="Victoria">Sabina Victoria</name><affiliation wicri:level="1"><nlm:aff id="aff1">Laboratory of Immunoregulation and Inflammation, Institut Pasteur de Montevideo, 11400 Montevideo, Uruguay</nlm:aff><country xml:lang="fr">Uruguay</country><wicri:regionArea>Laboratory of Immunoregulation and Inflammation, Institut Pasteur de Montevideo, 11400 Montevideo</wicri:regionArea><wicri:noRegion>11400 Montevideo</wicri:noRegion></affiliation></author><author><name sortKey="Veigas, Florencia" sort="Veigas, Florencia" uniqKey="Veigas F" first="Florencia" last="Veigas">Florencia Veigas</name><affiliation wicri:level="1"><nlm:aff id="aff3">Laboratories of Immunopathology and Translational Immuno-Oncology, Institute of Biology and Experimental Medicine (IBYME), National Council of Scientific and Technical Investigations (CONICET), C1428 Buenos Aires, Argentina</nlm:aff><country xml:lang="fr">Argentine</country><wicri:regionArea>Laboratories of Immunopathology and Translational Immuno-Oncology, Institute of Biology and Experimental Medicine (IBYME), National Council of Scientific and Technical Investigations (CONICET), C1428 Buenos Aires</wicri:regionArea><wicri:noRegion>C1428 Buenos Aires</wicri:noRegion></affiliation></author><author><name sortKey="Louvet, Cedric" sort="Louvet, Cedric" uniqKey="Louvet C" first="Cédric" last="Louvet">Cédric Louvet</name><affiliation wicri:level="4"><nlm:aff id="aff5">INSERM UMR 1064, Center for Research in Transplantation and Immunology, Université de Nantes, CHU Nantes, Institut de Transplantation Urologie Néphrologie (ITUN), 44093 Nantes, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>INSERM UMR 1064, Center for Research in Transplantation and Immunology, Université de Nantes, CHU Nantes, Institut de Transplantation Urologie Néphrologie (ITUN), 44093 Nantes</wicri:regionArea><placeName><region type="region" nuts="2">Pays de la Loire</region><settlement type="city">Nantes</settlement></placeName><orgName type="university">Université de Nantes</orgName></affiliation></author><author><name sortKey="Vanhove, Bernard" sort="Vanhove, Bernard" uniqKey="Vanhove B" first="Bernard" last="Vanhove">Bernard Vanhove</name><affiliation wicri:level="4"><nlm:aff id="aff5">INSERM UMR 1064, Center for Research in Transplantation and Immunology, Université de Nantes, CHU Nantes, Institut de Transplantation Urologie Néphrologie (ITUN), 44093 Nantes, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>INSERM UMR 1064, Center for Research in Transplantation and Immunology, Université de Nantes, CHU Nantes, Institut de Transplantation Urologie Néphrologie (ITUN), 44093 Nantes</wicri:regionArea><placeName><region type="region" nuts="2">Pays de la Loire</region><settlement type="city">Nantes</settlement></placeName><orgName type="university">Université de Nantes</orgName></affiliation><affiliation wicri:level="3"><nlm:aff id="aff6">Xenothera, 44093 Nantes, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Xenothera, 44093 Nantes</wicri:regionArea><placeName><region type="region" nuts="2">Pays de la Loire</region><settlement type="city">Nantes</settlement></placeName></affiliation></author><author><name sortKey="Floto, R Andres" sort="Floto, R Andres" uniqKey="Floto R" first="R. Andrés" last="Floto">R. Andrés Floto</name><affiliation wicri:level="4"><nlm:aff id="aff7">Molecular Immunity Unit, Department of Medicine, University of Cambridge, CB2 0QH Cambridge, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Molecular Immunity Unit, Department of Medicine, University of Cambridge, CB2 0QH Cambridge</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Anegon, Ignacio" sort="Anegon, Ignacio" uniqKey="Anegon I" first="Ignacio" last="Anegon">Ignacio Anegon</name><affiliation wicri:level="4"><nlm:aff id="aff5">INSERM UMR 1064, Center for Research in Transplantation and Immunology, Université de Nantes, CHU Nantes, Institut de Transplantation Urologie Néphrologie (ITUN), 44093 Nantes, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>INSERM UMR 1064, Center for Research in Transplantation and Immunology, Université de Nantes, CHU Nantes, Institut de Transplantation Urologie Néphrologie (ITUN), 44093 Nantes</wicri:regionArea><placeName><region type="region" nuts="2">Pays de la Loire</region><settlement type="city">Nantes</settlement></placeName><orgName type="university">Université de Nantes</orgName></affiliation></author><author><name sortKey="Cuturi, Maria Cristina" sort="Cuturi, Maria Cristina" uniqKey="Cuturi M" first="Maria Cristina" last="Cuturi">Maria Cristina Cuturi</name><affiliation wicri:level="4"><nlm:aff id="aff5">INSERM UMR 1064, Center for Research in Transplantation and Immunology, Université de Nantes, CHU Nantes, Institut de Transplantation Urologie Néphrologie (ITUN), 44093 Nantes, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>INSERM UMR 1064, Center for Research in Transplantation and Immunology, Université de Nantes, CHU Nantes, Institut de Transplantation Urologie Néphrologie (ITUN), 44093 Nantes</wicri:regionArea><placeName><region type="region" nuts="2">Pays de la Loire</region><settlement type="city">Nantes</settlement></placeName><orgName type="university">Université de Nantes</orgName></affiliation></author><author><name sortKey="Girotti, M Romina" sort="Girotti, M Romina" uniqKey="Girotti M" first="M. Romina" last="Girotti">M. Romina Girotti</name><affiliation wicri:level="1"><nlm:aff id="aff3">Laboratories of Immunopathology and Translational Immuno-Oncology, Institute of Biology and Experimental Medicine (IBYME), National Council of Scientific and Technical Investigations (CONICET), C1428 Buenos Aires, Argentina</nlm:aff><country xml:lang="fr">Argentine</country><wicri:regionArea>Laboratories of Immunopathology and Translational Immuno-Oncology, Institute of Biology and Experimental Medicine (IBYME), National Council of Scientific and Technical Investigations (CONICET), C1428 Buenos Aires</wicri:regionArea><wicri:noRegion>C1428 Buenos Aires</wicri:noRegion></affiliation></author><author><name sortKey="Rabinovich, Gabriel A" sort="Rabinovich, Gabriel A" uniqKey="Rabinovich G" first="Gabriel A." last="Rabinovich">Gabriel A. Rabinovich</name><affiliation wicri:level="1"><nlm:aff id="aff3">Laboratories of Immunopathology and Translational Immuno-Oncology, Institute of Biology and Experimental Medicine (IBYME), National Council of Scientific and Technical Investigations (CONICET), C1428 Buenos Aires, Argentina</nlm:aff><country xml:lang="fr">Argentine</country><wicri:regionArea>Laboratories of Immunopathology and Translational Immuno-Oncology, Institute of Biology and Experimental Medicine (IBYME), National Council of Scientific and Technical Investigations (CONICET), C1428 Buenos Aires</wicri:regionArea><wicri:noRegion>C1428 Buenos Aires</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff8">Department of Biological Chemistry, School of Exact and Natural Sciences, University of Buenos Aires, C1428 Buenos Aires, Argentina</nlm:aff><country xml:lang="fr">Argentine</country><wicri:regionArea>Department of Biological Chemistry, School of Exact and Natural Sciences, University of Buenos Aires, C1428 Buenos Aires</wicri:regionArea><wicri:noRegion>C1428 Buenos Aires</wicri:noRegion></affiliation></author><author><name sortKey="Hill, Marcelo" sort="Hill, Marcelo" uniqKey="Hill M" first="Marcelo" last="Hill">Marcelo Hill</name><affiliation wicri:level="1"><nlm:aff id="aff1">Laboratory of Immunoregulation and Inflammation, Institut Pasteur de Montevideo, 11400 Montevideo, Uruguay</nlm:aff><country xml:lang="fr">Uruguay</country><wicri:regionArea>Laboratory of Immunoregulation and Inflammation, Institut Pasteur de Montevideo, 11400 Montevideo</wicri:regionArea><wicri:noRegion>11400 Montevideo</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2">Immunobiology Department, Faculty of Medicine, University of the Republic, 11800 Montevideo, Uruguay</nlm:aff><country xml:lang="fr">Uruguay</country><wicri:regionArea>Immunobiology Department, Faculty of Medicine, University of the Republic, 11800 Montevideo</wicri:regionArea><wicri:noRegion>11800 Montevideo</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31085177</idno><idno type="pmc">6521897</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521897</idno><idno type="RBID">PMC:6521897</idno><idno type="doi">10.1016/j.ccell.2019.04.003</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000441</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000441</idno><idno type="wicri:Area/Pmc/Curation">000441</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000441</idno><idno type="wicri:Area/Pmc/Checkpoint">000352</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000352</idno><idno type="wicri:Area/Ncbi/Merge">000615</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Targeting TMEM176B Enhances Antitumor Immunity and Augments the Efficacy of Immune Checkpoint Blockers by Unleashing Inflammasome Activation</title><author><name sortKey="Segovia, Mercedes" sort="Segovia, Mercedes" uniqKey="Segovia M" first="Mercedes" last="Segovia">Mercedes Segovia</name><affiliation wicri:level="1"><nlm:aff id="aff1">Laboratory of Immunoregulation and Inflammation, Institut Pasteur de Montevideo, 11400 Montevideo, Uruguay</nlm:aff><country xml:lang="fr">Uruguay</country><wicri:regionArea>Laboratory of Immunoregulation and Inflammation, Institut Pasteur de Montevideo, 11400 Montevideo</wicri:regionArea><wicri:noRegion>11400 Montevideo</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2">Immunobiology Department, Faculty of Medicine, University of the Republic, 11800 Montevideo, Uruguay</nlm:aff><country xml:lang="fr">Uruguay</country><wicri:regionArea>Immunobiology Department, Faculty of Medicine, University of the Republic, 11800 Montevideo</wicri:regionArea><wicri:noRegion>11800 Montevideo</wicri:noRegion></affiliation></author><author><name sortKey="Russo, Sofia" sort="Russo, Sofia" uniqKey="Russo S" first="Sofia" last="Russo">Sofia Russo</name><affiliation wicri:level="1"><nlm:aff id="aff1">Laboratory of Immunoregulation and Inflammation, Institut Pasteur de Montevideo, 11400 Montevideo, Uruguay</nlm:aff><country xml:lang="fr">Uruguay</country><wicri:regionArea>Laboratory of Immunoregulation and Inflammation, Institut Pasteur de Montevideo, 11400 Montevideo</wicri:regionArea><wicri:noRegion>11400 Montevideo</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2">Immunobiology Department, Faculty of Medicine, University of the Republic, 11800 Montevideo, Uruguay</nlm:aff><country xml:lang="fr">Uruguay</country><wicri:regionArea>Immunobiology Department, Faculty of Medicine, University of the Republic, 11800 Montevideo</wicri:regionArea><wicri:noRegion>11800 Montevideo</wicri:noRegion></affiliation></author><author><name sortKey="Jeldres, Mathias" sort="Jeldres, Mathias" uniqKey="Jeldres M" first="Mathias" last="Jeldres">Mathias Jeldres</name><affiliation wicri:level="1"><nlm:aff id="aff1">Laboratory of Immunoregulation and Inflammation, Institut Pasteur de Montevideo, 11400 Montevideo, Uruguay</nlm:aff><country xml:lang="fr">Uruguay</country><wicri:regionArea>Laboratory of Immunoregulation and Inflammation, Institut Pasteur de Montevideo, 11400 Montevideo</wicri:regionArea><wicri:noRegion>11400 Montevideo</wicri:noRegion></affiliation></author><author><name sortKey="Mahmoud, Yamil D" sort="Mahmoud, Yamil D" uniqKey="Mahmoud Y" first="Yamil D." last="Mahmoud">Yamil D. Mahmoud</name><affiliation wicri:level="1"><nlm:aff id="aff3">Laboratories of Immunopathology and Translational Immuno-Oncology, Institute of Biology and Experimental Medicine (IBYME), National Council of Scientific and Technical Investigations (CONICET), C1428 Buenos Aires, Argentina</nlm:aff><country xml:lang="fr">Argentine</country><wicri:regionArea>Laboratories of Immunopathology and Translational Immuno-Oncology, Institute of Biology and Experimental Medicine (IBYME), National Council of Scientific and Technical Investigations (CONICET), C1428 Buenos Aires</wicri:regionArea><wicri:noRegion>C1428 Buenos Aires</wicri:noRegion></affiliation></author><author><name sortKey="Perez, Valentina" sort="Perez, Valentina" uniqKey="Perez V" first="Valentina" last="Perez">Valentina Perez</name><affiliation wicri:level="1"><nlm:aff id="aff1">Laboratory of Immunoregulation and Inflammation, Institut Pasteur de Montevideo, 11400 Montevideo, Uruguay</nlm:aff><country xml:lang="fr">Uruguay</country><wicri:regionArea>Laboratory of Immunoregulation and Inflammation, Institut Pasteur de Montevideo, 11400 Montevideo</wicri:regionArea><wicri:noRegion>11400 Montevideo</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2">Immunobiology Department, Faculty of Medicine, University of the Republic, 11800 Montevideo, Uruguay</nlm:aff><country xml:lang="fr">Uruguay</country><wicri:regionArea>Immunobiology Department, Faculty of Medicine, University of the Republic, 11800 Montevideo</wicri:regionArea><wicri:noRegion>11800 Montevideo</wicri:noRegion></affiliation></author><author><name sortKey="Duhalde, Maite" sort="Duhalde, Maite" uniqKey="Duhalde M" first="Maite" last="Duhalde">Maite Duhalde</name><affiliation wicri:level="1"><nlm:aff id="aff1">Laboratory of Immunoregulation and Inflammation, Institut Pasteur de Montevideo, 11400 Montevideo, Uruguay</nlm:aff><country xml:lang="fr">Uruguay</country><wicri:regionArea>Laboratory of Immunoregulation and Inflammation, Institut Pasteur de Montevideo, 11400 Montevideo</wicri:regionArea><wicri:noRegion>11400 Montevideo</wicri:noRegion></affiliation></author><author><name sortKey="Charnet, Pierre" sort="Charnet, Pierre" uniqKey="Charnet P" first="Pierre" last="Charnet">Pierre Charnet</name><affiliation wicri:level="3"><nlm:aff id="aff4">Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS ENSCM, Université de Montpellier, 34093 Montpellier, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS ENSCM, Université de Montpellier, 34093 Montpellier</wicri:regionArea><placeName><region type="region" nuts="2">Occitanie (région administrative)</region><region type="old region" nuts="2">Languedoc-Roussillon</region><settlement type="city">Montpellier</settlement></placeName></affiliation></author><author><name sortKey="Rousset, Matthieu" sort="Rousset, Matthieu" uniqKey="Rousset M" first="Matthieu" last="Rousset">Matthieu Rousset</name><affiliation wicri:level="3"><nlm:aff id="aff4">Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS ENSCM, Université de Montpellier, 34093 Montpellier, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS ENSCM, Université de Montpellier, 34093 Montpellier</wicri:regionArea><placeName><region type="region" nuts="2">Occitanie (région administrative)</region><region type="old region" nuts="2">Languedoc-Roussillon</region><settlement type="city">Montpellier</settlement></placeName></affiliation></author><author><name sortKey="Victoria, Sabina" sort="Victoria, Sabina" uniqKey="Victoria S" first="Sabina" last="Victoria">Sabina Victoria</name><affiliation wicri:level="1"><nlm:aff id="aff1">Laboratory of Immunoregulation and Inflammation, Institut Pasteur de Montevideo, 11400 Montevideo, Uruguay</nlm:aff><country xml:lang="fr">Uruguay</country><wicri:regionArea>Laboratory of Immunoregulation and Inflammation, Institut Pasteur de Montevideo, 11400 Montevideo</wicri:regionArea><wicri:noRegion>11400 Montevideo</wicri:noRegion></affiliation></author><author><name sortKey="Veigas, Florencia" sort="Veigas, Florencia" uniqKey="Veigas F" first="Florencia" last="Veigas">Florencia Veigas</name><affiliation wicri:level="1"><nlm:aff id="aff3">Laboratories of Immunopathology and Translational Immuno-Oncology, Institute of Biology and Experimental Medicine (IBYME), National Council of Scientific and Technical Investigations (CONICET), C1428 Buenos Aires, Argentina</nlm:aff><country xml:lang="fr">Argentine</country><wicri:regionArea>Laboratories of Immunopathology and Translational Immuno-Oncology, Institute of Biology and Experimental Medicine (IBYME), National Council of Scientific and Technical Investigations (CONICET), C1428 Buenos Aires</wicri:regionArea><wicri:noRegion>C1428 Buenos Aires</wicri:noRegion></affiliation></author><author><name sortKey="Louvet, Cedric" sort="Louvet, Cedric" uniqKey="Louvet C" first="Cédric" last="Louvet">Cédric Louvet</name><affiliation wicri:level="4"><nlm:aff id="aff5">INSERM UMR 1064, Center for Research in Transplantation and Immunology, Université de Nantes, CHU Nantes, Institut de Transplantation Urologie Néphrologie (ITUN), 44093 Nantes, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>INSERM UMR 1064, Center for Research in Transplantation and Immunology, Université de Nantes, CHU Nantes, Institut de Transplantation Urologie Néphrologie (ITUN), 44093 Nantes</wicri:regionArea><placeName><region type="region" nuts="2">Pays de la Loire</region><settlement type="city">Nantes</settlement></placeName><orgName type="university">Université de Nantes</orgName></affiliation></author><author><name sortKey="Vanhove, Bernard" sort="Vanhove, Bernard" uniqKey="Vanhove B" first="Bernard" last="Vanhove">Bernard Vanhove</name><affiliation wicri:level="4"><nlm:aff id="aff5">INSERM UMR 1064, Center for Research in Transplantation and Immunology, Université de Nantes, CHU Nantes, Institut de Transplantation Urologie Néphrologie (ITUN), 44093 Nantes, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>INSERM UMR 1064, Center for Research in Transplantation and Immunology, Université de Nantes, CHU Nantes, Institut de Transplantation Urologie Néphrologie (ITUN), 44093 Nantes</wicri:regionArea><placeName><region type="region" nuts="2">Pays de la Loire</region><settlement type="city">Nantes</settlement></placeName><orgName type="university">Université de Nantes</orgName></affiliation><affiliation wicri:level="3"><nlm:aff id="aff6">Xenothera, 44093 Nantes, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Xenothera, 44093 Nantes</wicri:regionArea><placeName><region type="region" nuts="2">Pays de la Loire</region><settlement type="city">Nantes</settlement></placeName></affiliation></author><author><name sortKey="Floto, R Andres" sort="Floto, R Andres" uniqKey="Floto R" first="R. Andrés" last="Floto">R. Andrés Floto</name><affiliation wicri:level="4"><nlm:aff id="aff7">Molecular Immunity Unit, Department of Medicine, University of Cambridge, CB2 0QH Cambridge, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Molecular Immunity Unit, Department of Medicine, University of Cambridge, CB2 0QH Cambridge</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Anegon, Ignacio" sort="Anegon, Ignacio" uniqKey="Anegon I" first="Ignacio" last="Anegon">Ignacio Anegon</name><affiliation wicri:level="4"><nlm:aff id="aff5">INSERM UMR 1064, Center for Research in Transplantation and Immunology, Université de Nantes, CHU Nantes, Institut de Transplantation Urologie Néphrologie (ITUN), 44093 Nantes, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>INSERM UMR 1064, Center for Research in Transplantation and Immunology, Université de Nantes, CHU Nantes, Institut de Transplantation Urologie Néphrologie (ITUN), 44093 Nantes</wicri:regionArea><placeName><region type="region" nuts="2">Pays de la Loire</region><settlement type="city">Nantes</settlement></placeName><orgName type="university">Université de Nantes</orgName></affiliation></author><author><name sortKey="Cuturi, Maria Cristina" sort="Cuturi, Maria Cristina" uniqKey="Cuturi M" first="Maria Cristina" last="Cuturi">Maria Cristina Cuturi</name><affiliation wicri:level="4"><nlm:aff id="aff5">INSERM UMR 1064, Center for Research in Transplantation and Immunology, Université de Nantes, CHU Nantes, Institut de Transplantation Urologie Néphrologie (ITUN), 44093 Nantes, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>INSERM UMR 1064, Center for Research in Transplantation and Immunology, Université de Nantes, CHU Nantes, Institut de Transplantation Urologie Néphrologie (ITUN), 44093 Nantes</wicri:regionArea><placeName><region type="region" nuts="2">Pays de la Loire</region><settlement type="city">Nantes</settlement></placeName><orgName type="university">Université de Nantes</orgName></affiliation></author><author><name sortKey="Girotti, M Romina" sort="Girotti, M Romina" uniqKey="Girotti M" first="M. Romina" last="Girotti">M. Romina Girotti</name><affiliation wicri:level="1"><nlm:aff id="aff3">Laboratories of Immunopathology and Translational Immuno-Oncology, Institute of Biology and Experimental Medicine (IBYME), National Council of Scientific and Technical Investigations (CONICET), C1428 Buenos Aires, Argentina</nlm:aff><country xml:lang="fr">Argentine</country><wicri:regionArea>Laboratories of Immunopathology and Translational Immuno-Oncology, Institute of Biology and Experimental Medicine (IBYME), National Council of Scientific and Technical Investigations (CONICET), C1428 Buenos Aires</wicri:regionArea><wicri:noRegion>C1428 Buenos Aires</wicri:noRegion></affiliation></author><author><name sortKey="Rabinovich, Gabriel A" sort="Rabinovich, Gabriel A" uniqKey="Rabinovich G" first="Gabriel A." last="Rabinovich">Gabriel A. Rabinovich</name><affiliation wicri:level="1"><nlm:aff id="aff3">Laboratories of Immunopathology and Translational Immuno-Oncology, Institute of Biology and Experimental Medicine (IBYME), National Council of Scientific and Technical Investigations (CONICET), C1428 Buenos Aires, Argentina</nlm:aff><country xml:lang="fr">Argentine</country><wicri:regionArea>Laboratories of Immunopathology and Translational Immuno-Oncology, Institute of Biology and Experimental Medicine (IBYME), National Council of Scientific and Technical Investigations (CONICET), C1428 Buenos Aires</wicri:regionArea><wicri:noRegion>C1428 Buenos Aires</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff8">Department of Biological Chemistry, School of Exact and Natural Sciences, University of Buenos Aires, C1428 Buenos Aires, Argentina</nlm:aff><country xml:lang="fr">Argentine</country><wicri:regionArea>Department of Biological Chemistry, School of Exact and Natural Sciences, University of Buenos Aires, C1428 Buenos Aires</wicri:regionArea><wicri:noRegion>C1428 Buenos Aires</wicri:noRegion></affiliation></author><author><name sortKey="Hill, Marcelo" sort="Hill, Marcelo" uniqKey="Hill M" first="Marcelo" last="Hill">Marcelo Hill</name><affiliation wicri:level="1"><nlm:aff id="aff1">Laboratory of Immunoregulation and Inflammation, Institut Pasteur de Montevideo, 11400 Montevideo, Uruguay</nlm:aff><country xml:lang="fr">Uruguay</country><wicri:regionArea>Laboratory of Immunoregulation and Inflammation, Institut Pasteur de Montevideo, 11400 Montevideo</wicri:regionArea><wicri:noRegion>11400 Montevideo</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2">Immunobiology Department, Faculty of Medicine, University of the Republic, 11800 Montevideo, Uruguay</nlm:aff><country xml:lang="fr">Uruguay</country><wicri:regionArea>Immunobiology Department, Faculty of Medicine, University of the Republic, 11800 Montevideo</wicri:regionArea><wicri:noRegion>11800 Montevideo</wicri:noRegion></affiliation></author></analytic><series><title level="j">Cancer Cell</title><idno type="ISSN">1535-6108</idno><idno type="eISSN">1878-3686</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Summary</title><p>Although immune checkpoint blockers have yielded significant clinical benefits in patients with different malignancies, the efficacy of these therapies is still limited. Here, we show that disruption of transmembrane protein 176B (TMEM176B) contributes to CD8<sup>+</sup> T cell-mediated tumor growth inhibition by unleashing inflammasome activation. Lack of <italic>Tmem176b</italic> enhances the antitumor activity of anti-CTLA-4 antibodies through mechanisms involving caspase-1/IL-1β activation. Accordingly, patients responding to checkpoint blockade therapies display an activated inflammasome signature. Finally, we identify BayK8644 as a potent TMEM176B inhibitor that promotes CD8<sup>+</sup> T cell-mediated tumor control and reinforces the antitumor activity of both anti-CTLA-4 and anti-PD-1 antibodies. Thus, pharmacologic de-repression of the inflammasome by targeting TMEM176B may enhance the therapeutic efficacy of immune checkpoint blockers.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Binnewies, M" uniqKey="Binnewies M">M. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Cancer Cell</journal-id><journal-id journal-id-type="iso-abbrev">Cancer Cell</journal-id><journal-title-group><journal-title>Cancer Cell</journal-title></journal-title-group><issn pub-type="ppub">1535-6108</issn><issn pub-type="epub">1878-3686</issn><publisher><publisher-name>Cell Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31085177</article-id><article-id pub-id-type="pmc">6521897</article-id><article-id pub-id-type="publisher-id">S1535-6108(19)30198-9</article-id><article-id pub-id-type="doi">10.1016/j.ccell.2019.04.003</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Targeting TMEM176B Enhances Antitumor Immunity and Augments the Efficacy of Immune Checkpoint Blockers by Unleashing Inflammasome Activation</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Segovia</surname><given-names>Mercedes</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="aff2" ref-type="aff">2</xref><xref rid="fn1" ref-type="fn">9</xref></contrib><contrib contrib-type="author"><name><surname>Russo</surname><given-names>Sofia</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="aff2" ref-type="aff">2</xref><xref rid="fn1" ref-type="fn">9</xref></contrib><contrib contrib-type="author"><name><surname>Jeldres</surname><given-names>Mathias</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Mahmoud</surname><given-names>Yamil D.</given-names></name><xref rid="aff3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>Perez</surname><given-names>Valentina</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Duhalde</surname><given-names>Maite</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Charnet</surname><given-names>Pierre</given-names></name><xref rid="aff4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>Rousset</surname><given-names>Matthieu</given-names></name><xref rid="aff4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>Victoria</surname><given-names>Sabina</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Veigas</surname><given-names>Florencia</given-names></name><xref rid="aff3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>Louvet</surname><given-names>Cédric</given-names></name><xref rid="aff5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>Vanhove</surname><given-names>Bernard</given-names></name><xref rid="aff5" ref-type="aff">5</xref><xref rid="aff6" ref-type="aff">6</xref></contrib><contrib contrib-type="author"><name><surname>Floto</surname><given-names>R. Andrés</given-names></name><xref rid="aff7" ref-type="aff">7</xref></contrib><contrib contrib-type="author"><name><surname>Anegon</surname><given-names>Ignacio</given-names></name><xref rid="aff5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>Cuturi</surname><given-names>Maria Cristina</given-names></name><email>ccuturi@nantes.inserm.fr</email><xref rid="aff5" ref-type="aff">5</xref><xref rid="fn2" ref-type="fn">10</xref><xref rid="cor1" ref-type="corresp">∗</xref></contrib><contrib contrib-type="author"><name><surname>Girotti</surname><given-names>M. Romina</given-names></name><xref rid="aff3" ref-type="aff">3</xref><xref rid="fn2" ref-type="fn">10</xref></contrib><contrib contrib-type="author"><name><surname>Rabinovich</surname><given-names>Gabriel A.</given-names></name><xref rid="aff3" ref-type="aff">3</xref><xref rid="aff8" ref-type="aff">8</xref><xref rid="fn2" ref-type="fn">10</xref></contrib><contrib contrib-type="author"><name><surname>Hill</surname><given-names>Marcelo</given-names></name><email>mhill@pasteur.edu.uy</email><xref rid="aff1" ref-type="aff">1</xref><xref rid="aff2" ref-type="aff">2</xref><xref rid="fn2" ref-type="fn">10</xref><xref rid="fn3" ref-type="fn">11</xref><xref rid="cor2" ref-type="corresp">∗∗</xref></contrib></contrib-group><aff id="aff1"><label>1</label>Laboratory of Immunoregulation and Inflammation, Institut Pasteur de Montevideo, 11400 Montevideo, Uruguay</aff><aff id="aff2"><label>2</label>Immunobiology Department, Faculty of Medicine, University of the Republic, 11800 Montevideo, Uruguay</aff><aff id="aff3"><label>3</label>Laboratories of Immunopathology and Translational Immuno-Oncology, Institute of Biology and Experimental Medicine (IBYME), National Council of Scientific and Technical Investigations (CONICET), C1428 Buenos Aires, Argentina</aff><aff id="aff4"><label>4</label>Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS ENSCM, Université de Montpellier, 34093 Montpellier, France</aff><aff id="aff5"><label>5</label>INSERM UMR 1064, Center for Research in Transplantation and Immunology, Université de Nantes, CHU Nantes, Institut de Transplantation Urologie Néphrologie (ITUN), 44093 Nantes, France</aff><aff id="aff6"><label>6</label>Xenothera, 44093 Nantes, France</aff><aff id="aff7"><label>7</label>Molecular Immunity Unit, Department of Medicine, University of Cambridge, CB2 0QH Cambridge, UK</aff><aff id="aff8"><label>8</label>Department of Biological Chemistry, School of Exact and Natural Sciences, University of Buenos Aires, C1428 Buenos Aires, Argentina</aff><author-notes><corresp id="cor1"><label>∗</label>Corresponding author <email>ccuturi@nantes.inserm.fr</email></corresp><corresp id="cor2"><label>∗∗</label>Corresponding author <email>mhill@pasteur.edu.uy</email></corresp><fn id="fn1"><label>9</label><p id="ntpara0010">These authors contributed equally</p></fn><fn id="fn2"><label>10</label><p id="ntpara0015">These authors contributed equally</p></fn><fn id="fn3"><label>11</label><p id="ntpara0020">Lead Contact</p></fn></author-notes><pub-date pub-type="pmc-release"><day>13</day><month>5</month><year>2019</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on .</pmc-comment>
<pub-date pub-type="ppub"><day>13</day><month>5</month><year>2019</year></pub-date><volume>35</volume><issue>5</issue><fpage>767</fpage><lpage>781.e6</lpage><history><date date-type="received"><day>21</day><month>6</month><year>2018</year></date><date date-type="rev-recd"><day>20</day><month>2</month><year>2019</year></date><date date-type="accepted"><day>10</day><month>4</month><year>2019</year></date></history><permissions><copyright-statement>© 2019 The Authors</copyright-statement><copyright-year>2019</copyright-year><license license-type="CC BY" xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).</license-p></license></permissions><abstract id="abs0010"><title>Summary</title><p>Although immune checkpoint blockers have yielded significant clinical benefits in patients with different malignancies, the efficacy of these therapies is still limited. Here, we show that disruption of transmembrane protein 176B (TMEM176B) contributes to CD8<sup>+</sup> T cell-mediated tumor growth inhibition by unleashing inflammasome activation. Lack of <italic>Tmem176b</italic> enhances the antitumor activity of anti-CTLA-4 antibodies through mechanisms involving caspase-1/IL-1β activation. Accordingly, patients responding to checkpoint blockade therapies display an activated inflammasome signature. Finally, we identify BayK8644 as a potent TMEM176B inhibitor that promotes CD8<sup>+</sup> T cell-mediated tumor control and reinforces the antitumor activity of both anti-CTLA-4 and anti-PD-1 antibodies. Thus, pharmacologic de-repression of the inflammasome by targeting TMEM176B may enhance the therapeutic efficacy of immune checkpoint blockers.</p></abstract><abstract abstract-type="author-highlights" id="abs0015"><title>Highlights</title><p><list list-type="simple" id="ulist0010"><list-item id="u0010"><label>•</label><p id="p0010">TMEM176B inhibits the NLRP3 inflammasome by controlling cytosolic Ca<sup>2+</sup>.</p></list-item><list-item id="u0015"><label>•</label><p id="p0015">Lack of <italic>Tmem176b</italic> enhances antitumor immunity via the caspase-1/IL-1β pathway</p></list-item><list-item id="u0020"><label>•</label><p id="p0020">Human tumors responding to immune checkpoint blockade display an inflammasome-activated signature</p></list-item><list-item id="u0025"><label>•</label><p id="p0025">A TMEM176B inhibitor improves the antitumor activity of immune checkpoint blockade</p></list-item></list></p></abstract><abstract abstract-type="teaser" id="abs0020"><p>Segovia et al. show that TMEM176B inhibits inflammasome activation and IL-1β cleavage by controlling cytosolic Ca<sup>2+</sup> in dendritic cells and macrophages. Inhibition of TMEM176B enhances tumor infiltration by CD8<sup>+</sup> T cells and improves the antitumor activity of immune checkpoint blockers.</p></abstract><kwd-group id="kwrds0010"><title>Keywords</title><kwd>TMEM176B</kwd><kwd>immune checkpoint blockers</kwd><kwd>cancer</kwd><kwd>inflammasome</kwd><kwd>dendritic cells</kwd><kwd>ion channel</kwd></kwd-group></article-meta><notes><p id="misc0010">Published: May 13, 2019</p></notes></front></pmc><affiliations><list><country><li>Argentine</li><li>France</li><li>Royaume-Uni</li><li>Uruguay</li></country><region><li>Angleterre</li><li>Angleterre de l'Est</li><li>Languedoc-Roussillon</li><li>Occitanie (région administrative)</li><li>Pays de la Loire</li></region><settlement><li>Cambridge</li><li>Montpellier</li><li>Nantes</li></settlement><orgName><li>Université de Cambridge</li><li>Université de Nantes</li></orgName></list><tree><country name="Uruguay"><noRegion><name sortKey="Segovia, Mercedes" sort="Segovia, Mercedes" uniqKey="Segovia M" first="Mercedes" last="Segovia">Mercedes Segovia</name></noRegion><name sortKey="Duhalde, Maite" sort="Duhalde, Maite" uniqKey="Duhalde M" first="Maite" last="Duhalde">Maite Duhalde</name><name sortKey="Hill, Marcelo" sort="Hill, Marcelo" uniqKey="Hill M" first="Marcelo" last="Hill">Marcelo Hill</name><name sortKey="Hill, Marcelo" sort="Hill, Marcelo" uniqKey="Hill M" first="Marcelo" last="Hill">Marcelo Hill</name><name sortKey="Jeldres, Mathias" sort="Jeldres, Mathias" uniqKey="Jeldres M" first="Mathias" last="Jeldres">Mathias Jeldres</name><name sortKey="Perez, Valentina" sort="Perez, Valentina" uniqKey="Perez V" first="Valentina" last="Perez">Valentina Perez</name><name sortKey="Perez, Valentina" sort="Perez, Valentina" uniqKey="Perez V" first="Valentina" last="Perez">Valentina Perez</name><name sortKey="Russo, Sofia" sort="Russo, Sofia" uniqKey="Russo S" first="Sofia" last="Russo">Sofia Russo</name><name sortKey="Russo, Sofia" sort="Russo, Sofia" uniqKey="Russo S" first="Sofia" last="Russo">Sofia Russo</name><name sortKey="Segovia, Mercedes" sort="Segovia, Mercedes" uniqKey="Segovia M" first="Mercedes" last="Segovia">Mercedes Segovia</name><name sortKey="Victoria, Sabina" sort="Victoria, Sabina" uniqKey="Victoria S" first="Sabina" last="Victoria">Sabina Victoria</name></country><country name="Argentine"><noRegion><name sortKey="Mahmoud, Yamil D" sort="Mahmoud, Yamil D" uniqKey="Mahmoud Y" first="Yamil D." last="Mahmoud">Yamil D. Mahmoud</name></noRegion><name sortKey="Girotti, M Romina" sort="Girotti, M Romina" uniqKey="Girotti M" first="M. Romina" last="Girotti">M. Romina Girotti</name><name sortKey="Rabinovich, Gabriel A" sort="Rabinovich, Gabriel A" uniqKey="Rabinovich G" first="Gabriel A." last="Rabinovich">Gabriel A. Rabinovich</name><name sortKey="Rabinovich, Gabriel A" sort="Rabinovich, Gabriel A" uniqKey="Rabinovich G" first="Gabriel A." last="Rabinovich">Gabriel A. Rabinovich</name><name sortKey="Veigas, Florencia" sort="Veigas, Florencia" uniqKey="Veigas F" first="Florencia" last="Veigas">Florencia Veigas</name></country><country name="France"><region name="Occitanie (région administrative)"><name sortKey="Charnet, Pierre" sort="Charnet, Pierre" uniqKey="Charnet P" first="Pierre" last="Charnet">Pierre Charnet</name></region><name sortKey="Anegon, Ignacio" sort="Anegon, Ignacio" uniqKey="Anegon I" first="Ignacio" last="Anegon">Ignacio Anegon</name><name sortKey="Cuturi, Maria Cristina" sort="Cuturi, Maria Cristina" uniqKey="Cuturi M" first="Maria Cristina" last="Cuturi">Maria Cristina Cuturi</name><name sortKey="Louvet, Cedric" sort="Louvet, Cedric" uniqKey="Louvet C" first="Cédric" last="Louvet">Cédric Louvet</name><name sortKey="Rousset, Matthieu" sort="Rousset, Matthieu" uniqKey="Rousset M" first="Matthieu" last="Rousset">Matthieu Rousset</name><name sortKey="Vanhove, Bernard" sort="Vanhove, Bernard" uniqKey="Vanhove B" first="Bernard" last="Vanhove">Bernard Vanhove</name><name sortKey="Vanhove, Bernard" sort="Vanhove, Bernard" uniqKey="Vanhove B" first="Bernard" last="Vanhove">Bernard Vanhove</name></country><country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Floto, R Andres" sort="Floto, R Andres" uniqKey="Floto R" first="R. Andrés" last="Floto">R. Andrés Floto</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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