Titre
Bcl-xL targeting eliminates ageing tumor-promoting neutrophils and inhibits lung tumor growth.
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Bodac, A.
Auteure/Auteur
Mayet, A.
Auteure/Auteur
Rana, S.
Auteure/Auteur
Pascual, J.
Auteure/Auteur
Bowler, A.D.
Auteure/Auteur
Roh, V.
Auteure/Auteur
Fournier, N.
Auteure/Auteur
Craciun, L.
Auteure/Auteur
Demetter, P.
Auteure/Auteur
Radtke, F.
Auteure/Auteur
Meylan, E.
Auteure/Auteur
Liens vers les unités
ISSN
1757-4684
Statut éditorial
Publié
Date de publication
2024-01
Volume
16
Numéro
1
Première page
158
Dernière page/numéro d’article
184
Peer-reviewed
Oui
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Publication Status: ppublish
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.
PID Serval
serval:BIB_B146DD2E08C2
PMID
Open Access
Oui
Date de création
2024-01-10T12:25:41.397Z
Date de création dans IRIS
2025-05-21T03:20:07Z
Fichier(s)![Vignette d'image]()
En cours de chargement...
Nom
38177532.pdf
Version du manuscrit
published
Licence
https://creativecommons.org/licenses/by/4.0
Taille
8.15 MB
Format
Adobe PDF
PID Serval
serval:BIB_B146DD2E08C2.P001
URN
urn:nbn:ch:serval-BIB_B146DD2E08C22
Somme de contrôle
(MD5):1ce77cdf01bb624eb261be3d711e9eb6