Certain tumor cells appear to make contact with immune cells. These are cells that normally keep the brain healthy. The tumor cells block the function of these immune cells. Two proteins are responsible for this blockage: one on the tumor cell and one on the immune cell. They are in contact with each other.
When the researchers stopped the interaction between the two proteins, they observed in the lab that the growth of tumor cells halted in tumor tissue samples from children, in mice, and in lab-grown mini‑tumors. They also saw that the tumors became smaller.
Stopping the interaction between the two proteins is a new starting point for developing a therapy that uses the immune system, also known as immunotherapy. As a next step, the researchers aim to begin developing such a therapy. The treatment should break down the protein on the tumor cells, so the immune cells are no longer blocked and can attack the tumor.
This research by the Rios and Stunnenberg groups was made possible in part by the KiKa Foundation (Kinderen Kankervrij), Oncode Institute, and the European Research Council.
Various researchers worldwide are working to find new opportunities for treating diffuse midline glioma (DMG). What is still lacking is a full understanding of immune–tumor cell interactions within their spatial context.
The research groups of Prof. Dr. Anne Rios, also affiliated with Oncode Institute, and Prof. Dr. Henk Stunnenberg tackled this question. They demonstrated that when the protein IGSFF11 is not expressed on the tumor cell, the local brain immune response can become active, resulting in tumor reduction. With this, they show that the IGSF11–VISTA signaling pathway is a promising new immunotherapeutic approach based on checkpoint inhibitors.
The results of this study were published today in Cancer Cell. PhD candidates Raphaël Collot (Rios group), Cristian Ruiz‑Moreno (Stunnenberg group), and Celina Honhoff (Rios group) conducted the research and share first authorship.
Multi‑omics approach
In the study, the researchers used a multi‑omics approach to map tumor–immune interactions and their spatial organization. They integrated single‑nuclei RNA sequencing, spatial transcriptomics, and high‑dimensional imaging. Using this approach, the team examined tumor tissue from 44 children and an experimental DMG mouse model. They found that IGSF11 on tumor cells interacts with VISTA, which is expressed on microglia.
Blocking
The researchers then blocked the IGSF11–VISTA signaling pathway using both genetic knockdown and anti‑VISTA blocking antibodies. They observed that the tumor shrank and that the lifespan of mice with DMG tumors increased. Microglia, the immune cells present in the brain, which were previously blocked by the signaling pathway, were responsible for this effect.
What the researchers found:
- DMG tumors consist of two different tumor regions that differ in their cellular composition:
- Regions defined by mesenchymal tumor cells and infiltrating immune cells.
- Regions enriched in astrocyte‑, oligodendrocyte‑, and oligodendrocyte precursor‑like tumor cell populations and local immune cells: microglia.
- Tumor cells in this second region express the relatively unknown immune checkpoint IGSF11. Through signaling to the VISTA protein, microglia are blocked; the immune system does not respond.
- Microglia are the immune cells that attack and control tumor cells in DMG when there is no IGSF11 expression. They are therefore not the T‑cells, which have been the main focus of research in relation to DMG until now.
Next steps
The research group of Anne Rios is focusing on better understanding how microglia attack the tumor cells when IGSF11–VISTA is blocked. Together with neuro‑oncologists at the Princess Máxima Center and other partners, her team is exploring how these findings can be translated into a new treatment for children with this currently incurable brain tumor.