Article ; Online: Bcl-xL targeting eliminates ageing tumor-promoting neutrophils and inhibits lung tumor growth.
2023 Volume 16, Issue 1, Page(s) 158–184
Abstract: 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 ... ...
| Abstract | 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. |
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| MeSH term(s) | Animals ; Humans ; Mice ; Aging ; Apoptosis ; Apoptosis Regulatory Proteins/metabolism ; bcl-X Protein ; Cell Line, Tumor ; Lung Neoplasms/pathology ; Neutropenia/drug therapy ; Neutropenia/metabolism ; Neutropenia/pathology ; Neutrophils/metabolism | |||||
| Chemical Substances | Apoptosis Regulatory Proteins ; bcl-X Protein ; Bcl2l1 protein, mouse | |||||
| Language | English | |||||
| Publishing date | 2023-12-20 | |||||
| Publishing country | England | |||||
| Document type | Journal Article | |||||
| ZDB-ID | 2467145-9 | |||||
| ISSN | 1757-4684 ; 1757-4676 | |||||
| ISSN (online) | 1757-4684 | |||||
| ISSN | 1757-4676 | |||||
| DOI | 10.1038/s44321-023-00013-x | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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