MARCH 24, 2025, NEW YORK – A Ludwig Cancer Research study has identified a key barrier to the efficacy of a promising combination of radiotherapy and immunotherapy for the treatment of brain metastases arising from breast cancer—and in doing so uncovered approaches to overcoming that resistance.
Seen in up to 30% of breast cancer patients, brain metastases (BrMs) are currently treated with precisely aimed beams of radiation that spare surrounding neural tissue. Upwards of 80% of brain tumors targeted with such “stereotactic radiosurgery” (SRS) respond to treatment, though new and untargeted metastatic growths—as well as cancer progression in other organs—typically limit patient survival to little more than a year.
Combining SRS with an immunotherapy known as immune checkpoint blockade (ICB) holds some promise in the treatment of BrMs, as analogous approaches employing chemotherapy and ICB have improved outcomes for advanced triple-negative breast cancer. With that in mind, researchers led by Ludwig Lausanne’s Johanna Joyce and alumnus Vladimir Wischnewski explored whether the combination therapy would improve the treatment of BrMs. They report in the current issue of Cell Reports that in mouse models, brain metastases of breast cancer resist this combination therapy even while tumors outside the cranium succumb to the treatment.
“We found that brain metastases of breast cancer cultivate a distinctive tumor microenvironment that profoundly inhibits anti-tumor immunity, even when it is boosted by immunotherapy,” said Joyce. “But our investigation also identified the cellular culprits that help create that immunosuppressive environment, uncovered useful molecular markers and generated gene expression data that should guide the design of new and improved treatments for BrMs, a major unmet need of breast cancer therapy.”
Joyce and her colleagues have shown that the immune system’s myeloid cells—especially tumor-associated macrophages, their brain-resident versions, microglia and neutrophils—establish a niche in the tumor microenvironment that regulates immunosuppression across metastatic and primary brain tumors. Though these cells have the potential to attack tumors, they are often reprogrammed by cancer cells to support tumor growth and suppress anti-tumor immune responses. The most potent responses of this kind are mediated by the immune system’s CD8+ T cells.
In the current study, Joyce, Wischnewski and colleagues developed a protocol to deliver SRS to mouse brain tumors in combination with ICB using anti-PD-1 antibodies, which disable the brakes that stop CD8+ T cells from killing their cellular targets. The rationale behind this combination is that radiotherapy destroys tumors in part by stimulating anti-tumor immunity. ICB thus has the potential to synergistically amplify the T cell arm of the SRS-induced immune assault on tumors.
As it turned out, this is indeed what happened when the SRS-ICB therapy was applied to primary breast tumors in a mouse model of breast cancer metastasis. When directed against breast cancer BrMs, however, the combination proved largely ineffective, even though the researchers could see that CD8+ T cells had flooded into the brain tumors and been engaged by anti-PD-1 antibodies.
“This suggested that something specific to the brain tumor microenvironment was inactivating the CD8+ T cells,” Wischnewski said. “Our analysis identified neutrophils and macrophages as those actors and showed that a subpopulation of these myeloid cells expressing particular genes were mainly responsible for the functional suppression of T cells in the brain metastases.”
Specifically, neutrophils expressing genes named S100a8 and a9 and macrophages expressing Trem2, a known suppressor of CD8+ T cell activity, were the main sources of T cell immune inhibition in ex vivo experiments. Myeloid cells with similar gene expression profiles have been linked in patients with other types of extracranial cancers to poor responses to ICB and shorter survival times.
“This research lays the foundation for devising immunotherapeutic strategies specifically designed to target brain metastases in breast cancer patients,” said Joyce. “But, more generally, it underscores the importance of tailoring such interventions to the distinct microenvironments of different types of brain tumors.”