PDL1 signals through conserved sequence motifs to overcome interferon-mediated cytotoxicity

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dc.contributor.authorGato Cañas, María
dc.contributor.authorZuazo Ibarra, Miren
dc.contributor.authorArasanz Esteban, Hugo
dc.contributor.authorIbañez Vea, María
dc.contributor.authorLorenzo, Laura
dc.contributor.authorFernández Hinojal, Gonzalo
dc.contributor.authorVera García, Ruth
dc.contributor.authorSmerdou, Cristian
dc.contributor.authorMartisova, Eva
dc.contributor.authorArozarena Martinicorena, Imanol
dc.contributor.authorWellbrock, Claudia
dc.contributor.authorLlopiz, Diana
dc.contributor.authorRuiz, Marta
dc.contributor.authorSarobe, Pablo
dc.contributor.authorBreckpot, Karine
dc.contributor.authorKochan, Grazyna
dc.contributor.authorEscors Murugarren, David
dc.contributor.departmentCiencias de la Saludes_ES
dc.contributor.departmentOsasun Zientziakeu
dc.contributor.funderUniversidad Pública de Navarra / Nafarroako Unibertsitate Publikoaes
dc.contributor.funderGobierno de Navarra / Nafarroako Gobernuaes
dc.date.accessioned2022-08-08T11:47:33Z
dc.date.available2022-08-08T11:47:33Z
dc.date.issued2017
dc.date.updated2022-08-08T11:05:19Z
dc.description.abstractPDL1 blockade produces remarkable clinical responses, thought to occur by T cell reactivation through prevention of PDL1-PD1 T cell inhibitory interactions. Here, we find that PDL1 cell-intrinsic signaling protects cancer cells from interferon (IFN) cytotoxicity and accelerates tumor progression. PDL1 inhibited IFN signal transduction through a conserved class of sequence motifs that mediate crosstalk with IFN signaling. Abrogation of PDL1 expression or antibody-mediated PDL1 blockade strongly sensitized cancer cells to IFN cytotoxicity through a STAT3/caspase-7-dependent pathway. Moreover, somatic mutations found in human carcinomas within these PDL1 sequence motifs disrupted motif regulation, resulting in PDL1 molecules with enhanced protective activities from type I and type II IFN cytotoxicity. Overall, our results reveal a mode of action of PDL1 in cancer cells as a first line of defense against IFN cytotoxicity.en
dc.description.sponsorshipThis project was funded by a crowdfunding project by FECYT (PRECIPITA, Spain), an FIS grant (PI14/00579) from the Instituto de Salud Carlos III, a grant from the Government of Navarre (Spain; BMED 033-2014), and a grant from Fundación Caixa (Spain) to G.K. We thank the SARAY Foundation (Navarra, Spain) and Sandra Ibarra’s foundation for financial support. M.G. is funded by a PhD fellowship granted by the Government of Navarre. M.Z. is funded by a fellowship granted by Universidad Pública de Navarra (UPNA), Spain. M.I.V. is funded by a Sara Borrel Fellowship. I.A. is funded by a Miguel Servet Fellowship. K.B. received funding from Kom Op Tegen Kanker (Belgium). We especially thank Luciano Escors, Lucia Murugarren, and family for their donations and overall support, as well as all the donors who contributed to the ‘PRECIPITA’ project. D.E. is funded by a Miguel Servet Fellowship (CP12/03114) awarded by the Instituto de Salud Carlos III (Spain).en
dc.format.mimetypeapplication/pdfen
dc.identifier.citationGato-Cañas, M.; Ibañez-Vea, M.; Zuazo, M.; Arasanz, H.; Lorenzo, L.; Fernandez-Hinojal, G.; Vera, R.; Smerdou, C.; Martisova, E.; Arozarena, I.; Wellbrock, C.; Llopiz, D.; Ruiz, M.; Sarobe, P.; Breckpot, K.; Kochan, G.; Escors, D.. (2017). PDL1 signals through conserved sequence motifs to overcome interferon-mediated cytotoxicity. Cell Reports. 20,8, pp. 1818-1829en
dc.identifier.doi10.1016/j.celrep.2017.07.075
dc.identifier.issn2211-1247
dc.identifier.urihttps://academica-e.unavarra.es/handle/2454/43728
dc.language.isoengen
dc.publisherElsevieren
dc.relation.ispartofCell Reports, 2017, 20 (8), pp. 1818-1829en
dc.relation.publisherversionhttps://doi.org/10.1016/j.celrep.2017.07.075
dc.rights© 2017 The Authors. This is an open access article under the CC BY-NC-ND licenseen
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectPDL1en
dc.subjectPD-L1en
dc.subjectB7-H1en
dc.subjectCD274en
dc.subjectPD1en
dc.subjectInterferonen
dc.subjectSignal transductionen
dc.subjectImmunotherapyen
dc.titlePDL1 signals through conserved sequence motifs to overcome interferon-mediated cytotoxicityen
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dspace.entity.typePublication
relation.isAuthorOfPublication193d800d-c38c-4627-b9d8-d29435d8214c
relation.isAuthorOfPublicationf96114c2-9fc5-4886-ab9a-4804f14aa9c6
relation.isAuthorOfPublication.latestForDiscovery193d800d-c38c-4627-b9d8-d29435d8214c

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