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

Over the next 12 months Dr Miller hopes to achieve:

• Increase the about of peripheral immune cells that are collected and analysed… so we can see if they are acting differently to the ones already in the brain

• Continue/finish profiling the proteins that are on the surface of the immune cells

• Combining all the data to discover and nominate the top therapeutic targets in their human tumour model system

Our thanks to Emily Conibear, an early career researcher, who volunteered her time and expertise to write this research summary.