Bcl-xL targeting eliminates ageing tumor-promoting neutrophils and inhibits lung tumor growth

Author:

Bodac Anita,Mayet Abdullah,Rana Sarika,Pascual Justine,Bowler Amber DORCID,Roh Vincent,Fournier NadineORCID,Craciun Ligia,Demetter Pieter,Radtke FreddyORCID,Meylan EtienneORCID

Abstract

AbstractElevated 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.

Funder

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung

Chercher et Trouver Foundation

Fonds De La Recherche Scientifique - FNRS

ULB Actions de Recherche Concertees

Fonds Jean Brachet

Association Jules Bordet

Publisher

Springer Science and Business Media LLC

Subject

Molecular Medicine

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