CSF1R inhibition is initially effective in treating preclinical models of breast-to-brain metastasis, but adaptive resistance can emerge via CSF2-STAT5 signalling. A new strategy, combining blockade of CSF1R and CSF2/STAT5 signaling offers a solution.
Tumor-associated macrophages and microglia (TAMs) constitute an abundant immune cell type in breast-to-brain metastases. In recent analyses of patient samples, researchers in the Joyce Lab implicated interactions between TAMs and T cells as potential mediators of immune evasion in brain metastases (BrM). In this study, they now show that targeting cancer-promoting TAMs using an inhibitor of colony stimulating factor-1 receptor (CSF1R), BLZ945, in preclinical breast-to-brain metastasis models reduces metastatic seeding and leads to anti-tumor responses in established brain metastases.
However, over time, the emergence of compensatory CSF2-STAT5-mediated pro-inflammatory TAM activation blunted the ultimate efficacy of CSF1R inhibition by inducing neuro-inflammation and wound repair gene signatures in TAMs - which fostered tumor progression. Critically, the combined blockade of CSF1R and CSF2/STAT5 signaling led to sustained tumor control, a normalization of TAM activation states, and amelioration of neuronal damage.
These results reveal the potential risk of unleashing pro-inflammatory responses in brain metastases following CSF1R inhibition, while also presenting experimental evidence for a compelling strategy to overcome this adaptive resistance mechanism. The findings thus have important translational implications when devising strategies to target the brain tumor microenvironment in patients.
The research* was conducted in collaboration with the Department of Neurosurgery at the Lausanne University Hospital (CHUV) and the Georg Speyer Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt-am-Main. It was jointly led by Johanna Joyce of the Department of Oncology UNIL CHUV, part of the Ludwig Lausanne branch, and Lisa Sevenich at Georg Speyer Haus.
Research for this project in the Joyce Lab was supported in part by the Breast Cancer Research Foundation, the Ludwig Institute for Cancer Research, the University of Lausanne, Cancer Research UK and the Swiss Cancer Research Foundation. Individual research fellowships from the German Research Foundation and Fondation Medic were awarded to Dr Florian Klemm, first author and former postdoctoral researcher of the Joyce Lab.
*Compensatory CSF2-driven macrophage activation promotes adaptive resistance to CSF1R inhibition in breast-to-brain metastasis