KAIST identifies why immune checkpoint inhibitors fail against brain tumors

South Korean researchers have identified why immune checkpoint inhibitors fail to work against brain tumors such as glioblastoma.

KAIST announced Sunday that a research team led by Lee Heung-kyu, a professor in the Department of Biological Sciences, has uncovered a new immune mechanism by which anti-CTLA-4 — a type of immune checkpoint inhibitor — activates B cells in the tumor-draining lymph nodes connected to the tumor, triggering an immune attack on brain tumors. Tumor-draining lymph nodes are where antigens from cancer cells first accumulate and immune responses begin; B cells are immune cells that produce antibodies to support immune responses.

Glioblastoma is one of the most aggressive malignant brain tumors, prone to recurrence and carrying a very poor prognosis even after surgery and radiation treatment. Immune checkpoint inhibitors, which restore immune cell function to attack cancer, have shown strong results across a range of cancers, but their effectiveness against glioblastoma has been limited by the powerful immunosuppressive environment surrounding the tumor.

T cells — immune cells that directly attack cancer cells — have long been considered the primary target of immune checkpoint inhibitors. B cells, by contrast, were well known for producing antibodies after vaccination, but their role in brain tumor immunotherapy had remained largely unexplored. The research team focused on the possibility that anti-CTLA-4 could affect not only T cells but B cells as well.

The experimental results overturned conventional thinking. In a mouse glioblastoma model, administering anti-CTLA-4 reduced tumor size and significantly improved survival rates. In mice lacking B cells, however, the same treatment produced almost none of these effects — demonstrating that B cells play an essential role in the therapeutic efficacy of immune checkpoint inhibitors.

The research team also identified where B cells carry out this activity. Rather than in the brain where the cancer cells reside, B cell responses increased markedly in the deep cervical lymph nodes — lymph nodes in the deep neck connected to the brain. In those lymph nodes, germinal center B cells and follicular helper T cells, both critical to antibody response formation, increased together, and this was linked to a subsequent rise in immunoglobulin G responses.

The IgG antibodies produced were found to bind to the surface of brain tumor cells, helping macrophages — immune cells that engulf foreign substances and cancer cells — eliminate cancer cells more effectively.

The research team also confirmed this process directly in living subjects. Using a specialized brain tumor model incorporating red fluorescent protein (mCherry) and green fluorescent protein (EGFP), they successfully observed macrophages actively eliminating brain tumor cells in vivo following immune checkpoint inhibitor treatment.

The study marks the first functional demonstration that B cell immune responses — previously known for their role in infection and vaccine responses — can be a key factor determining the effectiveness of immunotherapy against treatment-resistant brain tumors.

"These findings can be used to design immunotherapy strategies for treatment-resistant brain tumors, including glioblastoma," Lee said. "If we can identify the targets of antibodies that recognize brain tumors and develop technology to enhance lymph node-based B cell immune responses, this could advance into a next-generation immunotherapy strategy for glioblastoma and a range of other cancers."

He added that identifying which tumor antigens are recognized by antibodies that bind to brain tumors could, in the long term, inform the development of B cell-based vaccines or antibody treatments. "However, further validation will be needed before this can be applied to actual patient treatment — specifically, whether the same immune response occurs in human glioblastoma and under what combination conditions the therapeutic effect is enhanced," he said.

The findings were published in the international journal Science Immunology on July 10.