A study led by Ludwig Lausanne’s Johanna Joyce and alumnus Vladimir Wischnewski explains why brain metastases of breast cancer are likely to resist combinations of stereotactic radiosurgery (SRS) and immune checkpoint blockade (ICB) therapy. Radiotherapy destroys tumors in part by stimulating T cell-mediated anti-tumor immunity, suggesting a potential synergy with ICB. Indeed, analogous approaches employing chemotherapy and ICB have improved outcomes for advanced triple-negative breast cancer. Johanna, Vladimir and colleagues developed a new protocol to deliver cranial SRS to mice to model the therapy in the clinic and examined the therapeutic effects of its combination with anti-PD-1 ICB therapy in a mouse model of breast-to-brain metastasis. They reported in a March issue of Cell Reports that intracranial metastases in these models cultivate a highly immunosuppressive microenvironment, undermining the desired therapeutic synergy of the combination. They showed that a subset of myeloid immune cells—neutrophils expressing the inflammatory mediators S100a8 and a9, and macrophages and their brain-resident versions, microglia, expressing Trem2—suppresses the anti-tumor activity of CD8+ T cells that infiltrate these tumors. This occurs even when the combination therapy destroys primary breast tumors. The study opens the door to developing targeted treatments to address a major unmet need of breast cancer care.
The local microenvironment suppresses the synergy between irradiation and anti-PD1 therapy in breast-to-brain metastasis
Cell Reports, 2025 March 17