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Antagonistic inflammatory phenotypes dictate tumor fate and response to immune checkpoint blockade

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dc.contributor.authorBonavita, Eduardo
dc.contributor.authorBromley, Christian P.
dc.contributor.authorJonsson, Gustav
dc.contributor.authorPelly, Victoria S.
dc.contributor.authorSahoo, Sudhakar
dc.contributor.authorWalwyn-Brown, Katherine
dc.contributor.authorMensurado, Sofia
dc.contributor.authorMoeini, Agrin
dc.contributor.authorFlanagan, Eimear
dc.contributor.authorBell, Charlotte R.
dc.contributor.authorChiang, Shih-Chieh
dc.contributor.authorChikkanna Gowda, C.P.
dc.contributor.authorRogers, Neil
dc.contributor.authorSilva-Santos, Bruno
dc.contributor.authorJaillon, Sebastien
dc.contributor.authorMantovani, Alberto
dc.contributor.authorReis e Sousa, Caetano
dc.contributor.authorGuerra, Nadia
dc.contributor.authorDavis, Daniel M.
dc.contributor.authorZelenay, Santiago
dc.date.accessioned2021-04-06T13:25:25Z
dc.date.available2021-04-06T13:25:25Z
dc.date.issued2020
dc.description© 2020 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)pt_PT
dc.description.abstractInflammation can support or restrain cancer progression and the response to therapy. Here, we searched for primary regulators of cancer-inhibitory inflammation through deep profiling of inflammatory tumor microenvironments (TMEs) linked to immune-dependent control in mice. We found that early intratumoral accumulation of interferon gamma (IFN-γ)-producing natural killer (NK) cells induced a profound remodeling of the TME and unleashed cytotoxic T cell (CTL)-mediated tumor eradication. Mechanistically, tumor-derived prostaglandin E2 (PGE2) acted selectively on EP2 and EP4 receptors on NK cells, hampered the TME switch, and enabled immune evasion. Analysis of patient datasets across human cancers revealed distinct inflammatory TME phenotypes resembling those associated with cancer immune control versus escape in mice. This allowed us to generate a gene-expression signature that integrated opposing inflammatory factors and predicted patient survival and response to immune checkpoint blockade. Our findings identify features of the tumor inflammatory milieu associated with immune control of cancer and establish a strategy to predict immunotherapy outcomes.pt_PT
dc.description.sponsorshipThis work was supported by a Cancer Research UK Institute Award (A19258) to S.Z. We thank colleagues at CRUK Manchester Institute core facilities, in particular, Biological Resource Unit, Transgenic Breeding, Molecular Biology, Histology, and Flow Cytometry. E.B. was supported by an EMBO long-term fellowship ( ALTF-69-2016 ) and an EMBO advanced fellowship ( aALTF-638-2018 ). C.P.B. was funded by the National Institute for Health Research Manchester Biomedical Research Centre . G.J. was supported by a scholarship from The Society of Swedish Engineers in Great Britain . K.W.-B. was supported by a doctoral studentship from the Medical Research Council . C.R.e.S. was supported by The Francis Crick Institute , which receives core funding from Cancer Research UK ( FC001136 ), the UK Medical Research Council ( FC001136 ), and the Wellcome Trust ( FC001136 ), by an ERC Advanced Investigator grant ( AdG 268670 ), by a Wellcome Investigator Award ( WT106973MA ), and by a prize from the Louis-Jeantet Foundation . N.G. was supported by an Imperial Confidence in Concept Scheme ( RSRO_P71752 ). D.M.D. was supported by a Wellcome Trust Investigator Award ( 110091/Z/15/Z ).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationImmunity. 2020 Dec 15;53(6):1215-1229.e8.pt_PT
dc.identifier.doi10.1016/j.immuni.2020.10.020pt_PT
dc.identifier.eissn1097-4180
dc.identifier.issn1074-7613
dc.identifier.urihttp://hdl.handle.net/10451/47255
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherElsevierpt_PT
dc.relation.publisherversionhttps://www.cell.com/immunity/homept_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectNK cellspt_PT
dc.subjectCancer-related inflammationpt_PT
dc.subjectCytotoxic T cellspt_PT
dc.subjectImmune evasionpt_PT
dc.subjectimmunotherapypt_PT
dc.subjectInterferon-gammapt_PT
dc.subjectProstaglandin E2pt_PT
dc.subjectTumor immunitypt_PT
dc.subjectTumor microenvironmentpt_PT
dc.titleAntagonistic inflammatory phenotypes dictate tumor fate and response to immune checkpoint blockadept_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage1229.e8pt_PT
oaire.citation.issue6pt_PT
oaire.citation.startPage1215pt_PT
oaire.citation.titleImmunitypt_PT
oaire.citation.volume53pt_PT
person.familyNameSilva-Santos
person.givenNameBruno
person.identifier.ciencia-idD51E-6517-BE6A
person.identifier.orcid0000-0003-4141-9302
person.identifier.scopus-author-id6505885924
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublicationf313ff02-41ee-4014-88a1-bd641b6219bf
relation.isAuthorOfPublication.latestForDiscoveryf313ff02-41ee-4014-88a1-bd641b6219bf

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