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Primary tumors limit metastasis formation through induction of IL15-mediated cross-talk between patrolling monocytes and NK cells

2017Journal article Restricted access
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dc.contributor.authorKubo, Hiroshi
dc.contributor.authorMensurado, Sofia
dc.contributor.authorGonçalves-Sousa, Natacha
dc.contributor.authorSerre, Karine
dc.contributor.authorSilva-Santos, Bruno
dc.date.accessioned2022-09-08T14:17:21Z
dc.date.available2022-09-08T14:17:21Z
dc.date.issued2017
dc.description© 2017 American Association for Cancer Researchpt_PT
dc.description.abstractMetastases are responsible for the vast majority of cancer-related deaths. Although tumor cells can become invasive early during cancer progression, metastases formation typically occurs as a late event. How the immune response to primary tumors may dictate this outcome remains poorly understood, which hampers our capacity to manipulate it therapeutically. Here, we used a two-step experimental model, based on the highly aggressive B16F10 melanoma, that temporally segregates the establishment of primary tumors (subcutaneously) and the formation of lung metastases (from intravenous injection). This allowed us to identify a protective innate immune response induced by primary tumors that inhibits experimental metastasis. We found that in the presence of primary tumors, increased numbers of natural killer (NK) cells with enhanced IFNγ, granzyme B, and perforin production were recruited to the lung upon metastasis induction. These changes were mirrored by a local accumulation of patrolling monocytes and macrophages with high expression of MHC class II and NOS2. Critically, the protective effect on metastasis was lost upon patrolling monocyte or NK cell depletion, IL15 neutralization, or IFNγ ablation. The combined analysis of these approaches allowed us to establish a hierarchy in which patrolling monocytes, making IL15 in response to primary tumors, activate NK cells and IFNγ production that then inhibit lung metastasis formation. This work identifies an innate cell network and the molecular determinants responsible for "metastasis immunosurveillance," providing support for using the key molecular mediator, IL15, to improve immunotherapeutic outcomes.pt_PT
dc.description.sponsorshipThis work was funded by the European Research Council (CoG_646701 to B. Silva-Santos). S. Mensurado (PD/BD/114099/2015) and K. Serre (IF/00004/2014) acknowledge their individual funding from Fundação para a Ciência e Tecnologia.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationCancer Immunol Res. 2017 Sep;5(9):812-820pt_PT
dc.identifier.doi10.1158/2326-6066.CIR-17-0082pt_PT
dc.identifier.eissn2326-6074
dc.identifier.issn2326-6066
dc.identifier.urihttp://hdl.handle.net/10451/54385
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherAACR Journalspt_PT
dc.relationMicroRNA determinants of the balance between effector and regulatory T cells in vivo
dc.relationA designar
dc.relation.publisherversionhttps://aacrjournals.org/cancerimmunolrespt_PT
dc.titlePrimary tumors limit metastasis formation through induction of IL15-mediated cross-talk between patrolling monocytes and NK cellspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleMicroRNA determinants of the balance between effector and regulatory T cells in vivo
oaire.awardTitleA designar
oaire.awardURIinfo:eu-repo/grantAgreement/EC/H2020/646701/EU
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//PD%2FBD%2F114099%2F2015/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/Investigador FCT/IF%2F00004%2F2014%2FCP1236%2FCT0006/PT
oaire.citation.endPage820pt_PT
oaire.citation.issue9pt_PT
oaire.citation.startPage812pt_PT
oaire.citation.titleCancer Immunology Researchpt_PT
oaire.citation.volume5pt_PT
oaire.fundingStreamH2020
oaire.fundingStreamInvestigador FCT
person.familyNameMensurado Santos
person.familyNameGonçalves Silva Sousa
person.familyNameSerre
person.familyNameSilva-Santos
person.givenNameSofia
person.givenNameNatacha Maria
person.givenNameKarine
person.givenNameBruno
person.identifierhttps://scholar.google.com/citations?user=83kKWFAAAAAJ&hl=en&oi=ao
person.identifier120366
person.identifier.ciencia-idBA10-56F0-7CAD
person.identifier.ciencia-id8F19-8863-6B75
person.identifier.ciencia-id1E11-7283-DF35
person.identifier.ciencia-idD51E-6517-BE6A
person.identifier.orcid0000-0002-5157-0033
person.identifier.orcid0000-0001-5190-1122
person.identifier.orcid0000-0001-9152-4739
person.identifier.orcid0000-0003-4141-9302
person.identifier.scopus-author-id6602493849
person.identifier.scopus-author-id6505885924
project.funder.identifierhttp://doi.org/10.13039/501100008530
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameEuropean Commission
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsrestrictedAccesspt_PT
rcaap.typearticlept_PT
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