Why is tackling so-called cold colorectal cancers key to future treatments?

A new research project at the Institute of Genetics and Cancer aims to tackle the poor response of immune-cold colorectal cancers to immunotherapies.

Immune-cold tumours are those which don’t trigger a strong immune response and therefore don’t respond well to these therapies.

Dr Kevin Myant, who has been awarded a Discovery Programme Foundation Award of £1.5m from Cancer Research UK for the project ‘Leveraging RNA splicing inhibition to enhance efficacy of immunotherapies in immune-cold colorectal cancer’, says:

Colorectal cancer is quite difficult to treat. There are immunotherapies available which activate the immune system to identify colorectal cancer cells but these are notoriously poor performing in colorectal cancer. A small group of colorectal cancers respond really well and they can be cured. However, about 90% don’t respond at all. The reason they don’t respond is they don’t get recognised by the immune system. They don’t have many mutations and are so-called immune cold. The ones that do respond are immune hot. They have lots of mutations and this leads to recruitment of lots of immune cells. The purpose of this grant is to develop methods of making the immune cold colorectal cancers that currently don’t respond to the therapy, respond.

Previous research carried out by Kevin and his group found that if you disrupt a process called RNA splicing, you can activate an immune response.

We want to find out how and why disrupting RNA splicing activates an immune response and see if we can use this information to improve immunotherapy treatment. In its most simple form, it’s about making colorectal cancer cells visible to immune cells and respond to immunotherapy. If we can do this then we can start developing therapies which will allow that to be carried out in the clinic. We are very keen not just to understand why it happens and to show it’s possible to make it happen, but also to translate it into therapies.

Kevin Myant’s lab

The £1.5m award from CRUK will fund a fully self-contained lab, with two postdocs, a research assistant and a PhD student working on this project.

It’s an exciting area of research. Cancer research over the past 10 to 15 years was all about targeted therapies and precision medicine approaches. However, the more precise you are, the easier it is for cancer cells to develop resistance. What it is harder to find resistance against is things that activate immune responses. There’s a whole area of work in this field. How can you activate an immune response and why do some cancers respond to immune therapies and some don’t? It’s going to be a major focus of cancer research in the next decade – that and cancer prevention.

However, the project is not without its challenges.

The difficulty with RNA splicing is how do you target it safely? It happens in every cell and it’s something that’s difficult to target without being toxic. We think we have managed to develop a way that could work but that’s part of the proposal to test that. The biggest challenge in cancer is the high resistance to therapy in late-stage disease. We hope this research will lead to additional therapeutic options for these patients. If that happens it could have a big impact.

Another area of research Kevin’s lab has focused on, which was recently published in Nature, looked at the ‘shapeshifting’ ability of cancer cells to change form – a process known as cellular plasticity.

A key step in some aggressive forms of bowel cancer involve cancer cells losing their identity and mimicking cells from other parts of the body – such as skin or muscle cells – enabling them to spread.

We don’t know why that happens. One possibility is they are more robust, but there’s a fairly strong possibility it may also be related to immune response. They might be better at hiding from immune cells. The main theme linking the two projects is understanding how tumours spread and respond, or don’t respond, to therapy. That’s the main goal – understanding how that happens and make ways to get them to respond to immunotherapy, respond to the immune system.