ArticleEMBO molecular medicine2024
PD-1/LAG-3 co-signaling profiling uncovers CBL ubiquitin ligases as key immunotherapy targets.
Article in EMBO molecular medicine, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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The trial behind it
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Who cites it
13 citing papers in PubMed.
- Tumor-infiltrating lymphocytes display prognostic signatures associated with chemotherapy response in TNBC patients.iScience · 2026Article
- Targeting tumor-specific T cells with LAG3-directed interleukin-2 prevents T-cell exhaustion and reinvigorates antitumor immunity.Signal transduction and targeted therapy · 2026Article
- PD-1/LAG-3 signaling rewires T-cells via MYC inhibition.Signal transduction and targeted therapy · 2026Article
- Novel anti-LAG-3 antibody LBL-007 with anti-PD-1 blockade enhances antitumor immunity by promoting T cell-induced apoptosis.Scientific reports · 2025Article
- Proteostasis of immune checkpoint receptors.The Biochemical journal · 2025Review
- The Role of Immune Checkpoint Inhibitors in Cancer Therapy: Mechanism and Therapeutic Advances.MedComm · 2025Review
- Exploring new frontiers in LAG-3 biology and therapeutics.Trends in pharmacological sciences · 2025Review
- Tumour- and Non-Tumour-Associated Factors That Modulate Response to PD-1/PD-L1 Inhibitors in Non-Small Cell Lung Cancer.Cancers · 2025Review
- Programmed Death-1 Ligand 1 Domain Organization, Signaling Motifs, and Interactors in Cancer Immunotherapy.Cancers · 2025Review
- LAG3, TIM3 and TIGIT: New Targets for Immunotherapy and Potential Associations with Radiotherapy.Current oncology (Toronto, Ont.) · 2025Review
- Targeting Immune Checkpoint Inhibitors for Non-Small-Cell Lung Cancer: Beyond PD-1/PD-L1 Monoclonal Antibodies.Cancers · 2025Review
- Predictive biomarkers for immune checkpoint efficacy: is multi-omics breaking the deadlock?Translational lung cancer research · 2024Article
- Fractalkine in Health and Disease.International journal of molecular sciences · 2024Review
Corrections and comments
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Authors and funding
20 authors.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.