PD-1/LAG-3 co-signaling profiling uncovers CBL ubiquitin ligases as key immunotherapy targets

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dc.contributor.authorChocarro de Erauso, Luisa
dc.contributor.authorBlanco, Ester
dc.contributor.authorFernández-Rubio, Leticia
dc.contributor.authorGarnica, Maider
dc.contributor.authorZuazo Ibarra, Miren
dc.contributor.authorGarcía Granda, María Jesús
dc.contributor.authorBocanegra Gondán, Ana Isabel
dc.contributor.authorEchaide Górriz, Míriam
dc.contributor.authorJohnston, Colette
dc.contributor.authorEdwards, Carolyn J.
dc.contributor.authorLegg, James
dc.contributor.authorPierce, Andrew J.
dc.contributor.authorArasanz Esteban, Hugo
dc.contributor.authorFernández Hinojal, Gonzalo
dc.contributor.authorVera García, Ruth
dc.contributor.authorAusín, Karina
dc.contributor.authorSantamaría Martínez, Enrique
dc.contributor.authorFernández Irigoyen, Joaquín
dc.contributor.authorKochan, Grazyna
dc.contributor.authorEscors Murugarren, David
dc.contributor.departmentCiencias de la Saludes_ES
dc.contributor.departmentOsasun Zientziakeu
dc.date.accessioned2024-10-18T08:02:55Z
dc.date.available2024-10-18T08:02:55Z
dc.date.issued2024-07-19
dc.date.updated2024-10-18T07:40:10Z
dc.description.abstractMany cancer patients do not benefit from PD-L1/PD-1 blockade immunotherapies. PD-1 and LAG-3 co-upregulation in T-cells is one of the major mechanisms of resistance by establishing a highly dysfunctional state in T-cells. To identify shared features associated to PD-1/LAG-3 dysfunctionality in human cancers and T-cells, multiomic expression profiles were obtained for all TCGA cancers immune infiltrates. A PD-1/LAG-3 dysfunctional signature was found which regulated immune, metabolic, genetic, and epigenetic pathways, but especially a reinforced negative regulation of the TCR signalosome. These results were validated in T-cell lines with constitutively active PD-1, LAG-3 pathways and their combination. A differential analysis of the proteome of PD-1/LAG-3 T-cells showed a specific enrichment in ubiquitin ligases participating in E3 ubiquitination pathways. PD-1/LAG-3 co-blockade inhibited CBL-B expression, while the use of a bispecific drug in clinical development also repressed C-CBL expression, which reverted T-cell dysfunctionality in lung cancer patients resistant to PD-L1/PD-1 blockade. The combination of CBL-B-specific small molecule inhibitors with anti-PD-1/anti-LAG-3 immunotherapies demonstrated notable therapeutic efficacy in models of lung cancer refractory to immunotherapies, overcoming PD-1/LAG-3 mediated resistance. © The Author(s) 2024.en
dc.description.sponsorshipThis research was supported by: The Spanish Association against Cancer (AECC), PROYE16001ESCO; Instituto de Salud Carlos III (ISCIII)-FEDER Project grants FIS PI20/00010, FIS PI23/00196, COV20/00237, and TRANSPOCART ICI19/00069; Biomedicine Project Grant from the Department of Health of the Government of Navarre-FEDER funds (BMED 050-2019, 51-2021, 036-2023); Strategic projects from the Department of Industry, Government of Navarre (AGATA, Ref. 0011-1411-2020-000013; LINTERNA, Ref. 0011-1411-2020-000033; DESCARTHES, 0011-1411-2019-000058); European Union Horizon 2020 ISOLDA project, under grant agreement ID: 848166. LC is financed byInstituto de Salud Carlos III (ISCIII), co-financed by FEDER funds, "ContratosPFIS: contratos predoctorales de formación en investigación en salud" (FI21/00080); ME is financed by the Navarrabiomed-Fundación Miguel Servetpredoctoral contract.
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dc.format.mimetypeapplication/zipen
dc.identifier.citationChocarro, L., Blanco, E., Fernandez-Rubio, L., Garnica, M., Zuazo, M., Garcia, M. J., Bocanegra, A., Echaide, M., Johnston, C., Edwards, C. J., Legg, J., Pierce, A. J., Arasanz, H., Fernandez-Hinojal, G., Vera, R., Ausin, K., Santamaria, E., Fernandez-Irigoyen, J., Kochan, G., Escors, D. (2024). PD-1/LAG-3 co-signaling profiling uncovers CBL ubiquitin ligases as key immunotherapy targets. EMBO Molecular Medicine, 16(8), 1791-1816. https://doi.org/10.1038/s44321-024-00098-y.
dc.identifier.doi10.1038/s44321-024-00098-y
dc.identifier.issn1757-4676
dc.identifier.urihttps://academica-e.unavarra.es/handle/2454/52321
dc.language.isoeng
dc.publisherEMBO Press
dc.relation.ispartofEMBO Molecular Medicine (2024), vol. 16, núm. 8
dc.relation.projectIDinfo:eu-repo/grantAgreement/European Commission/Horizon 2020 Framework Programme/848166/
dc.relation.projectIDinfo:eu-repo/grantAgreement/ISCIII/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 (ISCIII)/PI20%2F00010/ES/
dc.relation.projectIDinfo:eu-repo/grantAgreement/ISCIII//PI23%2F00196/
dc.relation.projectIDinfo:eu-repo/grantAgreement/ISCIII//COV20%2F00237/
dc.relation.projectIDinfo:eu-repo/grantAgreement/ISCIII/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 (ISCIII)/ICI19%2F00069/ES/
dc.relation.projectIDinfo:eu-repo/grantAgreement/Gobierno de Navarra//050-2019/
dc.relation.projectIDinfo:eu-repo/grantAgreement/Gobierno de Navarra//51-2021/
dc.relation.projectIDinfo:eu-repo/grantAgreement/Gobierno de Navarra//036-2023/
dc.relation.projectIDinfo:eu-repo/grantAgreement/Gobierno de Navarra//0011-1411-2020-000013/
dc.relation.projectIDinfo:eu-repo/grantAgreement/Gobierno de Navarra//0011-1411-2020-000033/
dc.relation.projectIDinfo:eu-repo/grantAgreement/Gobierno de Navarra//0011-1411-2019-000058/
dc.relation.publisherversionhttps://doi.org/10.1038/s44321-024-00098-y
dc.rights© The Author(s) 2024. This article is licensed under a Creative Commons Attribution 4.0 International License.
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectCancer Immunotherapyen
dc.subjectCBL Ubiquitin Ligasesen
dc.subjectLAG-3en
dc.subjectPD-1en
dc.subjectT-cell Dysfunctionalityen
dc.titlePD-1/LAG-3 co-signaling profiling uncovers CBL ubiquitin ligases as key immunotherapy targetsen
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dspace.entity.typePublication
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relation.isAuthorOfPublication193d800d-c38c-4627-b9d8-d29435d8214c
relation.isAuthorOfPublicationabacfd17-2b93-4d99-bae2-52053d57401e
relation.isAuthorOfPublication86d1b76e-4790-40b1-a3ec-72331c5c6199
relation.isAuthorOfPublication.latestForDiscoveryfe5c362e-3c0c-4edb-aa2e-0de27c815ad2

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