Compensatory CSF2-driven macrophage activation promotes adaptive resistance to CSF1R inhibition in breast-to-brain metastasis.

Details

Serval ID
serval:BIB_E98C80E092F1
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Compensatory CSF2-driven macrophage activation promotes adaptive resistance to CSF1R inhibition in breast-to-brain metastasis.
Journal
Nature cancer
Author(s)
Klemm F., Möckl A., Salamero-Boix A., Alekseeva T., Schäffer A., Schulz M., Niesel K., Maas R.R., Groth M., Elie B.T., Bowman R.L., Hegi M.E., Daniel R.T., Zeiner P.S., Zinke J., Harter P.N., Plate K.H., Joyce J.A., Sevenich L.
ISSN
2662-1347 (Electronic)
ISSN-L
2662-1347
Publication state
Published
Issued date
10/2021
Peer-reviewed
Oui
Volume
2
Number
10
Pages
1086-1101
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
Tumor microenvironment-targeted therapies are emerging as promising treatment options for different cancer types. Tumor-associated macrophages and microglia (TAMs) represent an abundant nonmalignant cell type in brain metastases and have been proposed to modulate metastatic colonization and outgrowth. Here we demonstrate that targeting TAMs at distinct stages of the metastatic cascade using an inhibitor of colony-stimulating factor 1 receptor (CSF1R), BLZ945, in murine breast-to-brain metastasis models leads to antitumor responses in prevention and intervention preclinical trials. However, in established brain metastases, compensatory CSF2Rb-STAT5-mediated pro-inflammatory TAM activation blunted the ultimate efficacy of CSF1R inhibition by inducing neuroinflammation gene signatures in association with wound repair responses that fostered tumor recurrence. Consequently, blockade of CSF1R combined with inhibition of STAT5 signaling via AC4-130 led to sustained tumor control, a normalization of microglial activation states and amelioration of neuronal damage.
Keywords
Cancer Research, Oncology
Pubmed
Web of science
Create date
29/10/2021 17:42
Last modification date
13/02/2022 7:36
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