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

Klemm, F.; Schaeffer, A.; Salamero-Boix, A.; Alekseeva, T.; 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.

doi:10.1101/2021.06.07.447034

bioRxiv · 10.1101/2021.06.07.447034

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

Klemm, F.·Schaeffer, A.·Salamero-Boix, A.·Alekseeva, T.·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.

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Abstract

Tumor microenvironment-targeted therapies are emerging as promising treatment options for different cancer types. Tumor-associated macrophages and microglia (TAMs) represent an abundant non-malignant cell type in brain metastases and have been proposed to modulate metastatic colonization and outgrowth. We used an inhibitor of colony stimulating factor 1 receptor (CSF1R) to target TAMs at distinct stages of the metastatic cascade in preclinical breast-to-brain metastasis models and found that CSF1R inhibition leads to anti-tumor responses in prevention and intervention trials. However, in established brain metastases, compensatory CSF2Rb-STAT5-mediated pro-inflammatory TAM activation blunted the ultimate efficacy of CSF1R inhibition by inducing neuro-inflammation gene signatures in association with wound repair responses that fostered tumor recurrence. Consequently, combined blockade of CSF1R and STAT5 signaling led to sustained tumor control, a normalization of microglial activation states and amelioration of neuronal damage.

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Klemm, F., Schaeffer, A., Salamero-Boix, A., Alekseeva, T., 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.. 2021-06-07. Compensatory CSF2-driven macrophage activation promotes adaptive resistance to CSF1R inhibition in breast-to-brain metastasis. https://doi.org/10.1101/2021.06.07.447034

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