PD-1/LAG-3 co-signaling profiling uncovers CBL ubiquitin ligases as key immunotherapy targets.
CBL Ubiquitin Ligases
Cancer Immunotherapy
LAG-3
PD-1
T-cell Dysfunctionality
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: Germany
ID NLM: 101487380
Informations de publication
Date de publication:
19 Jul 2024
19 Jul 2024
Historique:
received:
12
01
2024
accepted:
21
06
2024
revised:
13
06
2024
medline:
20
7
2024
pubmed:
20
7
2024
entrez:
19
7
2024
Statut:
aheadofprint
Résumé
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.
Identifiants
pubmed: 39030301
doi: 10.1038/s44321-024-00098-y
pii: 10.1038/s44321-024-00098-y
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : MEC | Instituto de Salud Carlos III (ISCIII)
ID : FIS PI20/00010
Organisme : MEC | Instituto de Salud Carlos III (ISCIII)
ID : FIS PI23/00196
Organisme : MEC | Instituto de Salud Carlos III (ISCIII)
ID : COV20/00237
Organisme : MEC | Instituto de Salud Carlos III (ISCIII)
ID : FI21/00080
Organisme : MEC | Instituto de Salud Carlos III (ISCIII)
ID : TRANSPOCART ICI19/00069
Organisme : MEC | Instituto de Salud Carlos III (ISCIII)
ID : PFIS,FI21/00080
Organisme : Departamento de Salud, Gobierno de Navarra (Department of Health, Government of Navarra)
ID : BMED 050-2019
Organisme : Departamento de Salud, Gobierno de Navarra (Department of Health, Government of Navarra)
ID : BMED 51-2021
Organisme : Departamento de Salud, Gobierno de Navarra (Department of Health, Government of Navarra)
ID : BMED 036-2023
Organisme : Fundación Científica Asociación Española Contra el Cáncer (AECC)
ID : PROYE16001ESC
Organisme : Dirección General de Industria, Energia y Proyectos Estrategicos S3, Gobierno de Navarra (Department of Industry of the Government of Navarra)
ID : AGATA,0011-1411-2020-000013
Organisme : Dirección General de Industria, Energia y Proyectos Estrategicos S3, Gobierno de Navarra (Department of Industry of the Government of Navarra)
ID : LINTERNA,0011-1411-2020-000033
Organisme : Dirección General de Industria, Energia y Proyectos Estrategicos S3, Gobierno de Navarra (Department of Industry of the Government of Navarra)
ID : DESCARTHES,0011-1411-2019-000058
Organisme : Dirección General de Industria, Energia y Proyectos Estrategicos S3, Gobierno de Navarra (Department of Industry of the Government of Navarra)
ID : ARNMUNE,0011-1411-2023-000101
Organisme : EC | Horizon 2020 Framework Programme (H2020)
ID : ISOLDA,grant agreement 848166
Informations de copyright
© 2024. The Author(s).
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