PD-1/LAG-3 co-signaling profiling uncovers CBL ubiquitin ligases as key immunotherapy targets
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Published:2024-07-19
Issue:8
Volume:16
Page:1791-1816
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ISSN:1757-4684
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Container-title:EMBO Molecular Medicine
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language:en
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Short-container-title:EMBO Mol Med
Author:
Chocarro LuisaORCID, Blanco Ester, Fernandez-Rubio Leticia, Garnica MaiderORCID, Zuazo Miren, Garcia Maria Jesus, Bocanegra AnaORCID, Echaide Miriam, Johnston Colette, Edwards Carolyn J, Legg JamesORCID, Pierce Andrew JORCID, Arasanz HugoORCID, Fernandez-Hinojal Gonzalo, Vera RuthORCID, Ausin KarinaORCID, Santamaria Enrique, Fernandez-Irigoyen JoaquinORCID, Kochan GrazynaORCID, Escors DavidORCID
Abstract
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.
Funder
MEC | Instituto de Salud Carlos III Departamento de Salud, Gobierno de Navarra Fundación Científica Asociación Española Contra el Cáncer Dirección General de Industria, Energia y Proyectos Estrategicos S3, Gobierno de Navarra EC | Horizon 2020 Framework Programme
Publisher
Springer Science and Business Media LLC
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