Up to 20 percent of metastatic brain tumors arise from primary breast cancer.1 While primary breast cancer is curable if caught early, metastatic tumors have significantly poorer survival rates. Brain metastases, in particular, frequently fail to respond to standard-of-care treatments, even if those treatments are effective in the primary tumor that spawned them.
In a laboratory at the University of Lausanne, a team of researchers recently revealed some of the inner workings of brain metastases and how they resist treatment. Led by cancer biologist Johanna Joyce, the team demonstrated in a Cell Reports paper that the unique brain metastatic tumor microenvironment (TME) suppresses treatment responses by preventing killer T cells from doing their job.2
This microscopy image of brain metastasis tissue shows blood vessels (yellow) and cancer cells (grey nuclei), with infiltrating T cells (pink) in proximity to myeloid cells (blue) that contribute to creating an immune-suppressive microenvironment in the brain.
Johanna Joyce, University of Lausanne
“It really tells us it's not about the genetics [of the tumor],” said Joyce. “It's really about the microenvironment, and the brain microenvironment is profoundly more immune suppressive than in extracranial tumors.”
Joyce and her team are dedicated to the study of brain cancer and the brain TME, which is widely recognized to be immune-suppressed, or immunologically “cold.”3 The current study began after they made a key observation about the populations of immune cells present in patient samples.
In both primary brain tumors and brain metastases they found that the majority of immune cells were tumor-associated macrophages. In some types of brain metastases—notably breast-to-brain metastases—they were also infiltrated by neutrophils.4 To shed some light on the complexities of the breast-to-brain TME and what these cells were doing, the team turned to a mouse model, creating brain metastases using a primary breast cancer cell line.
The researchers first examined the abundance of T cells in the tumors. They found comparative numbers of T cells in the mice to those present in the human samples they had previously studied. When they depleted the T cells in the mice, they saw no effect on tumor control. This was strange because killer T cells were able to infiltrate the tumors, but they weren’t doing anything to stop them growing.
Joyce and her colleagues next wanted to examine the responses of these breast-to-brain metastases to a combination of therapies that has shown a synergistic effect in the treatment of extracranial tumors: targeted irradiation and immunotherapy targeting programmed cell death protein 1 (anti-PD-1). While there was a transient response to radiation alone, the tumors recurred quickly, and there was no synergistic effect when delivered in combination with anti-PD-1.
The group hypothesized that treatment resistance was to the brain TME, so they created tumors in the breast tissue of mice using cells from the same breast-to-brain metastases and exposed them to the same treatments. This allowed them to compare the responses of the different tumors without any genetic differences muddying the waters.
Cancer biologist Johanna Joyce and her team at the University of Lausanne have shed light on the complex microenvironment of metastatic brain tumors.
Johanna Joyce, University of Lausanne
Mice with breast tumors had significantly improved outcomes in response to treatment and exhibited an increase in pro-inflammatory factors like cytokines—a stark contrast to the mice bearing brain tumors. Joyce said it confirmed that something unique about how the brain TME was mediating treatment resistance: “The same cell line in different organ environments has completely opposite effects.”
To drill down further on what was causing these differences, they performed single-cell RNA sequencing of the immune cells present in the tumors. They found that tumor-associated macrophages found in the brain tumors had a unique immune-suppressive signature, including the upregulation of anti-inflammatory cytokines and metabolites that interfere with T cell function. A similar immune-suppressive signature was observed in neutrophils.
To gauge the impact of these potentially immune-suppressive cells on T cell function, the team co-cultured activated T cells with neutrophils that had been isolated either from the brain metastases, or from the bone marrow where they originate.
“Interestingly, we found that the neutrophils isolated from the brain metastases, but not the neutrophils isolated from the circulation, were able to suppress T cell proliferation,” explained Joyce. “That tells us that there's something about the education of those neutrophils once they arrive into the brain metastasis that's different from their progenitors.” The discovery of this vastly different function of neutrophils was a key result. “Our study was the first to show this in the brain, but also in tumors,” Joyce added.
The group also performed the same functional experiments with macrophages. “What we found is that the [tumor-associated macrophages] isolated from the primary breast tumor had a modest suppressive effect on T cell proliferation, but when we isolated their counterpart cells from brain metastases, this was much more striking,” remarked Joyce.
Delphine Merino, a cancer researcher at the Olivia Newton-John Cancer Research Institute who was not involved in the study, was enthusiastic about the results. “What's interesting in this study is that the authors go into the reason why immunotherapy and radiation are not so efficient in the brain, and that’s an important question,” said Merino.
Fortunately, the immune-suppressive signature the team identified in tumor-associated macrophages and neutrophils has revealed key targets that Joyce and her team plan to exploit to develop novel therapies for breast-to-brain metastases. Merino, who studies breast cancer metastases, said that these results could lead to better outcomes for a patient population with desperate unmet medical needs. “This kind of translational research is essential for the design of more effective and tolerable therapies,” she commented.
- Achrol AS, et al. Brain metastases. Nat Rev Dis Primer. 2019;5(1):1-26.
- Wischnewski V, et al. The local microenvironment suppresses the synergy between irradiation and anti-PD1 therapy in breast-to-brain metastasis. Cell Rep. 2025;44(3).
- Quail DF, Joyce JA. The microenvironmental landscape of brain tumors.Cancer Cell. 2017;31(3):326-341
- Maas RR, et al. The local microenvironment drives activation of neutrophils in human brain tumors.Cell. 2023;186(21):4546-4566.e27.
