Chocarro de Erauso, LuisaBlanco, EsterFernández-Rubio, LeticiaGarnica, MaiderZuazo Ibarra, MirenGarcía Granda, María JesúsBocanegra Gondán, Ana IsabelEchaide Górriz, MíriamJohnston, ColetteEdwards, Carolyn J.Legg, JamesPierce, Andrew J.Arasanz Esteban, HugoFernández Hinojal, GonzaloVera García, RuthAusín, KarinaSantamaría Martínez, EnriqueFernández Irigoyen, JoaquínKochan, GrazynaEscors Murugarren, David2024-10-182024-10-182024-07-19Chocarro, 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.1757-467610.1038/s44321-024-00098-yhttps://academica-e.unavarra.es/handle/2454/52321Many 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.application/pdfapplication/zipeng© The Author(s) 2024. This article is licensed under a Creative Commons Attribution 4.0 International License.Cancer ImmunotherapyCBL Ubiquitin LigasesLAG-3PD-1T-cell Dysfunctionalityinfo:eu-repo/semantics/article2024-10-18info:eu-repo/semantics/openAccess