Potent immune cells found in the vicinity of glioblastomas

Researchers from the German Cancer Consortium (DKTK) based at the West German Tumor Center Essen have made a surprising discovery about glioblastomas — highly aggressive, usually incurable brain tumours.

Until now, the body’s own defences have always been thought of as a holistic system that sends its troops to different parts of the body as required. However, the new data shows that highly potent immune cells gather in regional bone marrow niches close to the glioblastoma tumour and organise the defence from there. Their work has been published in the journal Nature Medicine.

Based on findings from animal experiments, the Essen team took tissue samples from the bone marrow near the tumour in the skull from untreated patients with glioblastoma. They found that bone marrow niches in close proximity to the glioblastoma appear to be the reservoir from which the anti-tumour defence is recruited.

Apart from active lymphoid stem cells that develop into immune cells, the researchers also found mature cytotoxic T lymphocytes (CD8 cells) in the bone marrow close to the tumour. As noted by first author Celia Dobersalske, “These are highly effective immune cells that play a central role in the defence against cancer”, as they can recognise and destroy malignant cells.

The CD8 cells in the bone marrow near the tumour had an increased number of receptors on their surface, which control the proliferation of mature T lymphocytes. In line with this, descendants of the same cell clones — one clone originates from one and the same cell — were detected both in the bone marrow and in the tumour tissue. This is clear evidence that the immune cells gathered onsite are fighting the glioblastoma.

“And they are successful — at least for a while,” said senior author Björn Scheffler. “We were able to show that the course of the disease correlates with the activity of the local CD8 cells.”

Not only does this finding turn conventional ideas about how the immune system works on their head, the treatment concepts for glioblastoma must also be reconsidered in light of the new data. As noted by Scheffler, “Until now, we hadn’t even considered the skullcap in our considerations. How could we, since there was no evidence that highly potent immune cells could be hiding there?”

“When we opened the skull, we may have destroyed important immune cells in the process,” added Ulrich Sure, a member of the Essen research team. “In view of the new findings, we find ourselves in a dilemma: we have to gain access to the tumour in order to remove it and also to be able to confirm the diagnosis. There is currently no other way than through the skull. But we are thinking about how we can minimise damage to the local bone marrow in the future.”

On the other hand, the discovery of the local immune system opens up opportunities for innovative therapies. In particular, so-called checkpoint inhibitors are coming back into play. These are immunotherapeutic agents that aim to boost the body’s own cancer defences, although they have to date shown little effect on glioblastomas.

“Various explanations have been suggested as an explanation, but perhaps we also need to rethink things in this respect,” Scheffler said. “We now know that highly potent immune cells are indeed present onsite. We were able to prove that they are fit to fight tumours, but they are not capable of destroying the tumour on their own. This is where we can start.

“One challenge will be to deliver drugs in sufficient concentration to the regional bone marrow niches at the right time. If we succeed, we may have a chance of controlling the growth of glioblastomas and improving our patients’ chances of survival.”

Image caption: Skull bone (grey) of a patient with glioblastoma, with vessels (red) in the inner cavities of the local bone marrow. The immune cells, which are only found enriched in the immediate vicinity of the tumour, are shown in green. Image ©Dobersalske/Scheffler/DKTK.