Bcl-xL targeting eliminates ageing tumor-promoting neutrophils and inhibits lung tumor growth.
Bcl-xL
Lung Adenocarcinoma
Mouse Models of Lung Cancer
Tumor-associated Neutrophils
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
20 Dec 2023
20 Dec 2023
Historique:
received:
28
06
2023
accepted:
28
11
2023
revised:
24
11
2023
medline:
5
1
2024
pubmed:
5
1
2024
entrez:
4
1
2024
Statut:
aheadofprint
Résumé
Elevated peripheral blood and tumor-infiltrating neutrophils are often associated with a poor patient prognosis. However, therapeutic strategies to target these cells are difficult to implement due to the life-threatening risk of neutropenia. In a genetically engineered mouse model of lung adenocarcinoma, tumor-associated neutrophils (TAN) demonstrate tumor-supportive capacities and have a prolonged lifespan compared to circulating neutrophils. Here, we show that tumor cell-derived GM-CSF triggers the expression of the anti-apoptotic Bcl-xL protein and enhances neutrophil survival through JAK/STAT signaling. Targeting Bcl-xL activity with a specific BH3 mimetic, A-1331852, blocked the induced neutrophil survival without impacting their normal lifespan. Specifically, oral administration with A-1331852 decreased TAN survival and abundance, and reduced tumor growth without causing neutropenia. We also show that G-CSF, a drug used to combat neutropenia in patients receiving chemotherapy, increased the proportion of young TANs and augmented the anti-tumor effect resulting from Bcl-xL blockade. Finally, our human tumor data indicate the same role for Bcl-xL on pro-tumoral neutrophil survival. These results altogether provide preclinical evidence for safe neutrophil targeting based on their aberrant intra-tumor longevity.
Identifiants
pubmed: 38177532
doi: 10.1038/s44321-023-00013-x
pii: 10.1038/s44321-023-00013-x
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (SNF)
ID : 310030_179324
Organisme : Fonds De La Recherche Scientifique - FNRS (FNRS)
ID : MISU F.6003.22
Organisme : Fonds De La Recherche Scientifique - FNRS (FNRS)
ID : TLV - 7.4574.21
Informations de copyright
© 2023. The Author(s).
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