Interleukin-34-Induced Arg1+ Macrophages Play a Key Role in Breast Cancer Brain Metastasis

Brain metastases occur in up to 40% of patients with stage IV breast cancer, and the cerebellum is a common site for metastases in HER2-positive breast cancer. We developed a syngeneic, immunocompetent mouse model of breast cancer brain metastases (BCBM) by stereotactically injecting murine breast cancer organoids into the cerebellum. Spatial transcriptomics on these brain metastases revealed that breast cancer cells produce interleukin-34 (IL34), which induces ARG1+ macrophages at the invading edge of metastases. IL34 expression in human brain metastasis samples was measured in two independent datasets, and IL34 was expressed widely in both HER2+ and HER2- human BCBM. Remarkably, IL34-deficient breast cancer cells failed to establish tumors in the mouse cerebellum. Furthermore, treatment with a blocking antibody against the IL34 receptor, CSF1R, led to tumor shrinkage, highlighting the translational potential of these findings, as a CSF1R-blocking antibody is FDA-approved for another indication, graft-versus-host disease.

Targeting IL34-CSF1R is a potential new approach to treat BCBM and could be combined with existing therapies. IL34 expression is widely found in human BCBM.