Researchers have discovered a clue as to why immune checkpoint inhibitors – cancer treatments that release the immune “brakes” that tumors exploit to evade attack – have limited effectiveness in some brain tumors. The KAIST research team has discovered that the antitumor effects of anti-CTLA-4 therapy depend not on T cells alone, but on the response of B cells and antibodies that begin in tumor-draining lymph nodes, opening a new avenue for the treatment of intractable brain tumors.
KAIST (Chairman Bae Choong-sik) announced on July 19 that a research team led by Professor Heung Gyu Lee of the School of Biological Sciences has identified a previously unrecognized immune mechanism in which anti-CTLA-4, a type of immune checkpoint inhibitor, promotes B cell responses in tumor-draining lymph nodes, thereby helping the immune system attack brain tumors.
Glioblastoma is one of the most aggressive malignant brain tumors, frequently recurs, and has a poor prognosis even after surgery and radiotherapy. Immune checkpoint inhibitors, which restore the ability of immune cells to attack cancer cells, have had substantial therapeutic effects in a variety of cancers. However, their efficacy against glioblastoma remains limited due to the highly immunosuppressive environment around the tumor.
Researchers have traditionally viewed T cells, immune cells that can directly attack cancer cells, as the primary target for immune checkpoint inhibitors. On the other hand, B cells are well known to produce antibodies after infection or vaccination, but their role in brain tumor immunotherapy remains largely unknown. The research team therefore investigated whether anti-CTLA-4 could affect not only T cell responses but also B cell responses.
This finding called into question the prevailing T cell-centric view. In a mouse glioma model, anti-CTLA-4 treatment reduced tumor burden and significantly prolonged survival. However, these therapeutic effects were largely abolished in mice lacking B cells, demonstrating that B cells are required for the efficacy of anti-CTLA-4 treatment in these models.
The research team also identified where B cells play an important role. This response was not so pronounced in the brain, where the tumor cells were, but was more markedly increased in the deep cervical lymph nodes, which are located deep in the neck and receive lymph fluid from the brain. Notably, germinal center B cells and follicular helper T cells, which are important for antibody formation, were increased together in these lymph nodes. This was accompanied by an increase in immunoglobulin G (IgG) responses. IgG is a major class of antibodies that can target and recognize cancer cells and help immune cells eliminate them.
The IgG antibodies produced bind to the surface of glioma cells and help macrophages, immune cells that engulf foreign substances and cancer cells, more effectively eliminate tumor cells.
The research team also investigated this process directly in vivo. Using a specialized dual-reporter glioma model that expresses the red fluorescent protein mCherry and the green fluorescent protein EGFP, researchers were able to visualize tumor-infiltrating phagocytes that actively engulf glioma cells after anti-CTLA-4 treatment.
This study provides the first functional evidence that the B-cell immune response, previously known primarily for its role in infections and vaccination, can be a key factor in determining the effectiveness of immunotherapy against difficult-to-treat brain tumors. We also extend the traditional T-cell-centric framework of cancer immunotherapy by showing that therapeutic effects can be strongly shaped by immune responses generated not only within the tumor but also from tumor-draining lymph nodes outside the tumor.
Yumin Kim, a postdoctoral researcher in the KAIST School of Biological Sciences, served as the study’s first author, and Professor Heung Kyyu Lee served as corresponding author. Professor Ji Eun Oh of the KAIST Graduate School of Medical Science and Engineering also contributed to the research. The findings were published in the magazine on July 10th. scientific immunology.
sauce:
Korea Advanced Institute of Science and Technology (KAIST)
Reference magazines:
DOI: 10.1126/sciimmunol.adz2494
