Skull Immune Structures May Provide First Response Against Brain Cancer

For decades, scientists assumed that the brain and the immune system did not communicate. A study by researchers at Washington University School of Medicine (WashU Medicine) in St. Louis has now revealed that the brain not only communicates with the immune system but also has positioned immune “security stations” nearby.

The team discovered lymph node-like structures in the skull bone marrow of mice for the first time and demonstrated that they act as rapid first responders against brain cancer before distant lymph nodes get the signal that abnormal cells are present. The researchers also found evidence of similar immune cells in human skull bone marrow. The study is the first to find such immune hubs in bone.

“This study reveals that the skull bone marrow is far more than just a structural framework—it harbors previously unrecognized hubs for brain-specific immune responses,” said Jonathan Kipnis, PhD, the Alan A. and Edith L. Wolff Distinguished Professor of Pathology & Immunology and a BJC Investigator at WashU Medicine. “Uncovering this localized immune niche changes how we view neuroimmune interactions and opens exciting new avenues for treating brain tumors and other neurological diseases.”

Kipnis is senior author of the researchers’ published paper in Nature, titled “Functional role of skull lymphoid structures in CNS immunosurveillance.”

The Kipnis lab challenged the once widely accepted idea that the brain is shielded from the immune system when they discovered lymphatic vessels running through the dura mater, the outer tissue layer enveloping the brain underneath the skull. More recently, the team identified tiny physical channels bridging the skull, dura, and brain tissue, revealing a direct conduit for immune cells and cellular waste to move between the brain and local skull bone marrow. “Recent findings reveal that channels between the skull and the dura mater facilitate the exchange of cerebrospinal fluid and immune cells between the CNS and skull bone marrow of mice under both homeostatic and disease conditions,” the authors wrote in their newly published paper in Nature.

However, they pointed out, while accumulating evidence demonstrates that the CNS is not disconnected from the peripheral immune system, “… precisely how the adaptive immune system surveils the CNS remains a critical question … Skull bone marrow functions as a source of immune cells for the CNS5, yet its role in CNS antigen-specific adaptive immune responses remains unclear.”

For their newly reported research in mice, the team tracked the movement of proteins from the brain through the channels directly into the skull’s bone marrow, where they uncovered immune-system structures typically found in the lymph nodes. These act as the immune system’s training hub where T follicular helper (T_FH) immune cells assist B cells in creating large amounts of antibodies that help fight disease and infection. “…we demonstrate that the skull BM of mice contains cellular components that are characteristic of peripheral lymphoid organs,” they wrote. “We have never seen such structures in healthy bone marrow before,” said Jang Hyun Park, PhD, the study’s first author and a postdoctoral research fellow in the Kipnis lab who is starting his own lab at the Korea Advanced Institute of Science and Technology this year. “It is an exciting discovery that points out that a complex brain requires its own specialized immune structures to defend it.”

To test whether these nearby hubs actively protect against brain disease, the team used a model of glioblastoma, an aggressive form of brain cancer. They found that in mice with brain cancer, disrupting the skull immune hubs with a drug caused tumors to grow faster than in mice with intact hubs. Impairing their function caused a drop in survival, showing that the brain actively relies on these local centers for defense against cancer.

The researchers also developed a targeted therapy designed to supercharge antibody production inside the skull marrow. By delivering the mixture of the three immune-boosting proteins using a gel applied directly under the scalp, the researchers prompted a wave of tumor-fighting immune responses to attack the cancer. These responses, the research found, occurred first in the immune hubs in the skull bone marrow, then later in nearby lymph nodes outside the skull. Mice given the gel experienced better tumor rejection and lived longer compared with control mice. The collective data, the team wrote, “… indicate that skull-targeting CD40 agonism combined with administration of the IL-21 and IFNγ supports IgG responses in the skull BM and subsequently enhances intratumoural microglial, NK and CD8+ T cell anti-tumor responses while attenuating suppressive immune cells.”

Kipnis said, “The finding fundamentally changes our current understanding of neuroimmunology. Knowing that the brain relies on first responders in the surrounding skull for defense has the potential to change how we think about developing therapies for many neurological conditions, including Alzheimer’s disease, Parkinson’s disease, schizophrenia, long COVID, and many others that have an immune component to them. Such therapies could access these immune hubs directly through the skull, without major peripheral side effects.”