Lymphatic vessels regulate immune microenvironments in human and murine melanoma
Identifieur interne : 012C15 ( Main/Exploration ); précédent : 012C14; suivant : 012C16Lymphatic vessels regulate immune microenvironments in human and murine melanoma
Auteurs : Amanda W. Lund [États-Unis, Suisse] ; Marek Wagner [Norvège] ; Manuel Fankhauser [Suisse] ; Eli S. Steinskog [Norvège] ; Maria A. Broggi [Suisse] ; Stefani Spranger ; Thomas F. Gajewski [États-Unis] ; Kari Alitalo [Finlande] ; Hans P. Eikesdal [Norvège] ; Helge Wiig [Norvège] ; Melody A. Swartz [Suisse, États-Unis]Source :
- The Journal of Clinical Investigation [ 0021-9738 ] ; ????.
Abstract
Lymphatic remodeling in tumor microenvironments correlates with progression and metastasis, and local lymphatic vessels play complex and poorly understood roles in tumor immunity. Tumor lymphangiogenesis is associated with increased immune suppression, yet lymphatic vessels are required for fluid drainage and immune cell trafficking to lymph nodes, where adaptive immune responses are mounted. Here, we examined the contribution of lymphatic drainage to tumor inflammation and immunity using a mouse model that lacks dermal lymphatic vessels (K14-VEGFR3-Ig mice). Melanomas implanted in these mice grew robustly, but exhibited drastically reduced cytokine expression and leukocyte infiltration compared with those implanted in control animals. In the absence of local immune suppression, transferred cytotoxic T cells more effectively controlled tumors in K14-VEGFR3-Ig mice than in control mice. Furthermore, gene expression analysis of human melanoma samples revealed that patient immune parameters are markedly stratified by levels of lymphatic markers. This work suggests that the establishment of tumor-associated inflammation and immunity critically depends on lymphatic vessel remodeling and drainage. Moreover, these results have implications for immunotherapies, the efficacies of which are regulated by the tumor immune microenvironment.
Url:
DOI: 10.1172/JCI79434
PubMed: 27525437
PubMed Central: 5004967
Affiliations:
- Finlande, Norvège, Suisse, États-Unis
- Canton de Vaud, Illinois, Oregon, Uusimaa
- Helsinki, Lausanne
- Université d'Helsinki
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Le document en format XML
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Lund</name><affiliation wicri:level="2"><nlm:aff id="A1">Department of Cell, Developmental and Cancer Biology and Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Department of Cell, Developmental and Cancer Biology and Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon</wicri:regionArea><placeName><region type="state">Oregon</region></placeName></affiliation><affiliation wicri:level="3"><nlm:aff id="A2">Institute of Bioengineering and Swiss Institute of Experimental Cancer Research (ISREC), Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Suisse</country><wicri:regionArea>Institute of Bioengineering and Swiss Institute of Experimental Cancer Research (ISREC), Ecole Polytechnique Federale de Lausanne, Lausanne</wicri:regionArea><placeName><settlement type="city">Lausanne</settlement><region nuts="3" type="region">Canton de Vaud</region></placeName></affiliation></author><author><name sortKey="Wagner, Marek" sort="Wagner, Marek" uniqKey="Wagner M" first="Marek" last="Wagner">Marek Wagner</name><affiliation wicri:level="1"><nlm:aff id="A3">Department of Biomedicine, University of Bergen, Bergen, Norway.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Norvège</country><wicri:regionArea>Department of Biomedicine, University of Bergen, Bergen</wicri:regionArea><wicri:noRegion>Bergen</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="A4">Department of Pathology, Haukeland University Hospital, Bergen, Norway.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Norvège</country><wicri:regionArea>Department of Pathology, Haukeland University Hospital, Bergen</wicri:regionArea><wicri:noRegion>Bergen</wicri:noRegion></affiliation></author><author><name sortKey="Fankhauser, Manuel" sort="Fankhauser, Manuel" uniqKey="Fankhauser M" first="Manuel" last="Fankhauser">Manuel Fankhauser</name><affiliation wicri:level="3"><nlm:aff id="A2">Institute of Bioengineering and Swiss Institute of Experimental Cancer Research (ISREC), Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Suisse</country><wicri:regionArea>Institute of Bioengineering and Swiss Institute of Experimental Cancer Research (ISREC), Ecole Polytechnique Federale de Lausanne, Lausanne</wicri:regionArea><placeName><settlement type="city">Lausanne</settlement><region nuts="3" type="region">Canton de Vaud</region></placeName></affiliation></author><author><name sortKey="Steinskog, Eli S" sort="Steinskog, Eli S" uniqKey="Steinskog E" first="Eli S." last="Steinskog">Eli S. Steinskog</name><affiliation wicri:level="1"><nlm:aff id="A3">Department of Biomedicine, University of Bergen, Bergen, Norway.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Norvège</country><wicri:regionArea>Department of Biomedicine, University of Bergen, Bergen</wicri:regionArea><wicri:noRegion>Bergen</wicri:noRegion></affiliation></author><author><name sortKey="Broggi, Maria A" sort="Broggi, Maria A" uniqKey="Broggi M" first="Maria A." last="Broggi">Maria A. Broggi</name><affiliation wicri:level="3"><nlm:aff id="A2">Institute of Bioengineering and Swiss Institute of Experimental Cancer Research (ISREC), Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Suisse</country><wicri:regionArea>Institute of Bioengineering and Swiss Institute of Experimental Cancer Research (ISREC), Ecole Polytechnique Federale de Lausanne, Lausanne</wicri:regionArea><placeName><settlement type="city">Lausanne</settlement><region nuts="3" type="region">Canton de Vaud</region></placeName></affiliation></author><author><name sortKey="Spranger, Stefani" sort="Spranger, Stefani" uniqKey="Spranger S" first="Stefani" last="Spranger">Stefani Spranger</name><affiliation><nlm:aff wicri:cut=" and" id="A5">Department of Pathology</nlm:aff></affiliation></author><author><name sortKey="Gajewski, Thomas F" sort="Gajewski, Thomas F" uniqKey="Gajewski T" first="Thomas F." last="Gajewski">Thomas F. Gajewski</name><affiliation><nlm:aff wicri:cut=" and" id="A5">Department of Pathology</nlm:aff></affiliation><affiliation wicri:level="2"><nlm:aff id="A6">Department of Medicine, University of Chicago, Chicago, Illinois, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Department of Medicine, University of Chicago, Chicago, Illinois</wicri:regionArea><placeName><region type="state">Illinois</region></placeName></affiliation></author><author><name sortKey="Alitalo, Kari" sort="Alitalo, Kari" uniqKey="Alitalo K" first="Kari" last="Alitalo">Kari Alitalo</name><affiliation wicri:level="4"><nlm:aff id="A7">Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Finlande</country><wicri:regionArea>Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki</wicri:regionArea><orgName type="university">Université d'Helsinki</orgName><placeName><settlement type="city">Helsinki</settlement><region type="région" nuts="2">Uusimaa</region></placeName><placeName><settlement type="city">Helsinki</settlement><region type="région" nuts="2">Uusimaa</region></placeName><orgName type="university">Université d'Helsinki</orgName></affiliation></author><author><name sortKey="Eikesdal, Hans P" sort="Eikesdal, Hans P" uniqKey="Eikesdal H" first="Hans P." last="Eikesdal">Hans P. Eikesdal</name><affiliation wicri:level="1"><nlm:aff id="A8">Section of Oncology, Department of Clinical Science, University of Bergen, Bergen, Norway.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Norvège</country><wicri:regionArea>Section of Oncology, Department of Clinical Science, University of Bergen, Bergen</wicri:regionArea><wicri:noRegion>Bergen</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="A9">Department of Oncology, Haukeland University Hospital, Bergen, Norway.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Norvège</country><wicri:regionArea>Department of Oncology, Haukeland University Hospital, Bergen</wicri:regionArea><wicri:noRegion>Bergen</wicri:noRegion></affiliation></author><author><name sortKey="Wiig, Helge" sort="Wiig, Helge" uniqKey="Wiig H" first="Helge" last="Wiig">Helge Wiig</name><affiliation wicri:level="1"><nlm:aff id="A3">Department of Biomedicine, University of Bergen, Bergen, Norway.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Norvège</country><wicri:regionArea>Department of Biomedicine, University of Bergen, Bergen</wicri:regionArea><wicri:noRegion>Bergen</wicri:noRegion></affiliation></author><author><name sortKey="Swartz, Melody A" sort="Swartz, Melody A" uniqKey="Swartz M" first="Melody A." last="Swartz">Melody A. Swartz</name><affiliation wicri:level="3"><nlm:aff id="A2">Institute of Bioengineering and Swiss Institute of Experimental Cancer Research (ISREC), Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Suisse</country><wicri:regionArea>Institute of Bioengineering and Swiss Institute of Experimental Cancer Research (ISREC), Ecole Polytechnique Federale de Lausanne, Lausanne</wicri:regionArea><placeName><settlement type="city">Lausanne</settlement><region nuts="3" type="region">Canton de Vaud</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="A10">Institute for Molecular Engineering, University of Chicago, Chicago, Illinois, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Institute for Molecular Engineering, University of Chicago, Chicago, Illinois</wicri:regionArea><placeName><region type="state">Illinois</region></placeName></affiliation></author></analytic><series><title level="j">The Journal of Clinical Investigation</title><idno type="ISSN">0021-9738</idno><idno type="eISSN">1558-8238</idno><imprint><date when="????">????</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Lymphatic remodeling in tumor microenvironments correlates with progression and metastasis, and local lymphatic vessels play complex and poorly understood roles in tumor immunity. Tumor lymphangiogenesis is associated with increased immune suppression, yet lymphatic vessels are required for fluid drainage and immune cell trafficking to lymph nodes, where adaptive immune responses are mounted. Here, we examined the contribution of lymphatic drainage to tumor inflammation and immunity using a mouse model that lacks dermal lymphatic vessels (K14-VEGFR3-Ig mice). Melanomas implanted in these mice grew robustly, but exhibited drastically reduced cytokine expression and leukocyte infiltration compared with those implanted in control animals. In the absence of local immune suppression, transferred cytotoxic T cells more effectively controlled tumors in K14-VEGFR3-Ig mice than in control mice. Furthermore, gene expression analysis of human melanoma samples revealed that patient immune parameters are markedly stratified by levels of lymphatic markers. This work suggests that the establishment of tumor-associated inflammation and immunity critically depends on lymphatic vessel remodeling and drainage. Moreover, these results have implications for immunotherapies, the efficacies of which are regulated by the tumor immune microenvironment.</p></div></front></TEI><affiliations><list><country><li>Finlande</li><li>Norvège</li><li>Suisse</li><li>États-Unis</li></country><region><li>Canton de Vaud</li><li>Illinois</li><li>Oregon</li><li>Uusimaa</li></region><settlement><li>Helsinki</li><li>Lausanne</li></settlement><orgName><li>Université d'Helsinki</li></orgName></list><tree><noCountry><name sortKey="Spranger, Stefani" sort="Spranger, Stefani" uniqKey="Spranger S" first="Stefani" last="Spranger">Stefani Spranger</name></noCountry><country name="États-Unis"><region name="Oregon"><name sortKey="Lund, Amanda W" sort="Lund, Amanda W" uniqKey="Lund A" first="Amanda W." last="Lund">Amanda W. Lund</name></region><name sortKey="Gajewski, Thomas F" sort="Gajewski, Thomas F" uniqKey="Gajewski T" first="Thomas F." last="Gajewski">Thomas F. Gajewski</name><name sortKey="Swartz, Melody A" sort="Swartz, Melody A" uniqKey="Swartz M" first="Melody A." last="Swartz">Melody A. Swartz</name></country><country name="Suisse"><region name="Canton de Vaud"><name sortKey="Lund, Amanda W" sort="Lund, Amanda W" uniqKey="Lund A" first="Amanda W." last="Lund">Amanda W. Lund</name></region><name sortKey="Broggi, Maria A" sort="Broggi, Maria A" uniqKey="Broggi M" first="Maria A." last="Broggi">Maria A. Broggi</name><name sortKey="Fankhauser, Manuel" sort="Fankhauser, Manuel" uniqKey="Fankhauser M" first="Manuel" last="Fankhauser">Manuel Fankhauser</name><name sortKey="Swartz, Melody A" sort="Swartz, Melody A" uniqKey="Swartz M" first="Melody A." last="Swartz">Melody A. 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Steinskog</name><name sortKey="Wagner, Marek" sort="Wagner, Marek" uniqKey="Wagner M" first="Marek" last="Wagner">Marek Wagner</name><name sortKey="Wiig, Helge" sort="Wiig, Helge" uniqKey="Wiig H" first="Helge" last="Wiig">Helge Wiig</name></country><country name="Finlande"><region name="Uusimaa"><name sortKey="Alitalo, Kari" sort="Alitalo, Kari" uniqKey="Alitalo K" first="Kari" last="Alitalo">Kari Alitalo</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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