1. PD-1/LAG-3 co-signaling profiling uncovers CBL ubiquitin ligases as key immunotherapy targets
- Author
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Luisa Chocarro, Ester Blanco, Leticia Fernandez-Rubio, Maider Garnica, Miren Zuazo, Maria Jesus Garcia, Ana Bocanegra, Miriam Echaide, Colette Johnston, Carolyn J Edwards, James Legg, Andrew J Pierce, Hugo Arasanz, Gonzalo Fernandez-Hinojal, Ruth Vera, Karina Ausin, Enrique Santamaria, Joaquin Fernandez-Irigoyen, Grazyna Kochan, and David Escors
- Subjects
Cancer Immunotherapy ,CBL Ubiquitin Ligases ,LAG-3 ,PD-1 ,T-cell Dysfunctionality ,Medicine (General) ,R5-920 ,Genetics ,QH426-470 - Abstract
Abstract Many 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.
- Published
- 2024
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