Researchers have uncovered a clue to why immune checkpoint inhibitors—cancer therapies that release the immune brakes exploited by tumours to evade attack—show limited efficacy in some brain tumours.
A KAIST research team found that B cell and antibody responses initiated in tumour-draining lymph nodes, rather than T cells alone, are critical to the antitumour effects of anti-CTLA-4 therapy, opening a new avenue for treating intractable brain tumours.
The team led by Heung Kyu Lee from the Department of Biological Sciences identified a previously unrecognised immune mechanism through which anti-CTLA-4, a type of immune checkpoint inhibitor, promotes B-cell responses in tumour-draining lymph nodes, thereby helping the immune system attack brain tumours.
Glioblastoma is one of the most aggressive malignant brain tumours, with frequent recurrence and a poor prognosis even after surgery and radiation therapy. Immune checkpoint inhibitors, which restore the ability of immune cells to attack cancer cells, have produced substantial therapeutic benefits in various cancers. However, their effectiveness in glioblastoma has remained limited because of the highly immunosuppressive environment surrounding the tumour.
Researchers have traditionally regarded T cells—immune cells that can directly attack cancer cells—as the primary target of immune checkpoint inhibitors. B cells, meanwhile, are well known for producing antibodies following infection or vaccination, but their role in brain tumour immunotherapy has remained largely unexplored. The research team therefore investigated whether anti-CTLA-4 could influence B-cell responses as well as T-cell responses.
The findings challenged the prevailing T-cell-centred view. In mouse glioma models, anti-CTLA-4 treatment reduced tumour burden and significantly prolonged survival. However, these therapeutic effects were largely lost in mice lacking B cells, demonstrating that B cells are required for the efficacy of anti-CTLA-4 treatment in these models.
The team also identified where B cells played their key role. Rather than being prominent in the brain, where the tumour cells were located, the response increased markedly in the deep cervical lymph nodes, which are located deep in the neck and receive lymphatic drainage from the brain. Germinal centre B cells and T follicular helper cells, both of which are important for antibody formation, increased together in these lymph nodes. This was accompanied by an increase in immunoglobulin G, or IgG, responses. IgG is a major class of antibody that can recognise cancer cells as targets and help immune cells eliminate them.
The resulting IgG antibodies bound to the surface of glioma cells, helping macrophages—immune cells that engulf foreign substances and cancer cells—remove the tumour cells more effectively.
The research team also examined this process directly in vivo. Using a specialised dual-reporter glioma model expressing the red fluorescent protein mCherry and the green fluorescent protein EGFP, the researchers successfully visualised tumour-infiltrating phagocytes actively engulfing glioma cells following anti-CTLA-4 treatment.
The study provides the first functional evidence that B-cell immune responses—previously known mainly for their roles in infection and vaccination—can be a key factor determining the effectiveness of immunotherapy for hard-to-treat brain tumours. It also expands the conventional T-cell-centred framework of cancer immunotherapy by showing treatment efficacy can be strongly shaped by immune responses originating not only within the tumour, but also in tumour-draining lymph nodes outside it.
Yumin Kim, a postdoctoral researcher in the KAIST Department of Biological Sciences, was first author of the study, with Heung Kyu Lee the corresponding author. Ji Eun Oh from the KAIST Graduate School of Medical Science and Engineering also contributed to the research. The findings were published in Science Immunology.