Understanding how immune cells block glioblastoma treatments

Fast facts

• Official title: Targeting the innate immune system to fight glioblastoma
• Lead researcher: Dr Tyler Miller
• Where: Massachusetts General Hospital
• When: October 2020 – September 2023
• Cost: £180,000 over three years
• Research type: Adult, High Grade, Glioblastoma, Immunotherapy, Academic
• Award type: Future leaders

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Progress update: In just the first year of his three-year grant, Dr Miller has been able to distinguish differences between immune cells that fight against the tumour and those that are making the brain a tumour-friendly environment. This new knowledge will help him focus on testing which drugs (immunotherapies) can turn the whole immune system against the tumour.

What is it?

Recently, new immunotherapies (treatments that manipulate the immune system to attack tumours) have shown huge success in many cancers. Unfortunately, these revolutionary therapies have failed to induce a response in brain tumour patients. This is believed to be due to large populations of immunosuppressive cells being present in the tumour, as these prevent other immune cells (especially T cells) from accessing and subsequently killing the brain tumour. These immunosuppressive cells are referred to as tumour-associated myeloid cells(TAMs).

Currently, we don’t know where these TAMs come from or what they do. Because of this, we’re unsure how they’re blocking other immune cells from attacking brain tumours.

To learn more about where the TAMs come from, Dr Miller and his team have developed a new technology that can trace the origins of single cells. This technology makes use of DNA from mitochondria (the part of the cell that generates energy).

Because of the way that mitochondrial DNA changes, cells with similar mitochondrial DNA are likely to have come from the same place. This new technology is able to compare the mitochondrial DNA found in different areas of the tumour or the person’s blood, giving us an indication of their origins.

Alongside this new technology, Dr Miller will also be measuring what RNA and proteins are present in TAMs. Like DNA, RNA and protein are codes that can tell us more about a cell’s function. Once we better understand how TAMs work, we can then try to prevent them from blocking other immune cells from attacking brain tumours.

Overall, using these techniques Dr Miller and his team will:

1. determine the origin of the TAMs found in glioblastomas
2. understand the function of these TAMs
3. model the interactions that these TAMs have with other immune cells, as this will mean researchers can try and block their immunosuppressive effects.

If we could inhibit the functions of these immunosuppressive cells, we could render brain tumours sensitive to breakthrough immunotherapies that have thus far been ineffective for brain tumour patients.

Dr Tyler Miller

Why is it important?

Glioblastomas are the most aggressive type of brain tumour with extremely poor survival rates. Therefore, more research is desperately needed to discover new ways to harness the power of the immune system to help fight glioblastomas.

By characterising the TAMs found in glioblastomas, Dr Miller’s team could not only enable the manipulation of current immunotherapies to benefit brain tumours, but also potentially identify new immunotherapeutic treatments.

If new ways of manipulating TAMs are discovered, Dr Miller aims to progress his work to the clinic with the support of our Research Involvement Network.

Who will it help?

This study aims to help adults who are diagnosed with glioblastomas in the future.

However, TAMs are present in lots of brain tumours, so this project also has the potential to improve our understanding of how the immune system interacts with brain tumours more generally – potentially providing evidence to jump start further research in other tumour types.

Milestones

• Dr Miller studied different types of immune cells – called “myeloid cells” – in gliomas, identifying 14 distinct programmes that define cell type and cell behaviour. Some of these programmes prevent the immune system from attacking the tumour the way they should. These results have highlighted potential treatment targets to reduce this suppression of the immune system.
• The team revealed that many of these myeloid cells in brain tumours come from cells that were circulating in the blood before infiltrating the tumour. This is an important finding because it suggests that it may be possible to target these cells prior to them entering the tumour, where it is difficult for some treatments to reach due to the blood- brain barrier.
• Dr Miller has also developed a cutting-edge method to study brain tumours and confirmed important signals or ‘markers’ on the immune cells, making it easier to understand how they work, and how these cells interact with each other and influence activity. 
• These findings were tested in a model that mimics brain tumours called a “glioblastoma organoid model”,. and Dr Miller is continuing his work to understand how these signals can influence immune cell behaviour in the context of brain tumours.
• Another discovery highlights that the commonly used steroid, dexamethasone, can lead to more immunosuppressive myeloid cells. This finding may impact how medical professionals approach steroid administration in brain tumour patients in the future.

Further Research

Dr Tyler Miller has recently been awarded the Junior Fellows Award.