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The secret in cancer cells that can make immunotherapy more effective

Tim Gunn
by Tim Gunn | Analysis

31 January 2024

2 comments 2 comments

Cells with nuclei in blue and mitochondria (energy factories) in green.
Changes to mitochondria (green) in cancer cells can increase immunotherapy success rates. (Credit: National Institutes of Health)


Scientists at the Cancer Research UK Scotland Institute have discovered that certain mutations can make cancers much more likely to respond to immunotherapy. By mimicking the effects of those changes, we could make breakthrough drugs work for many more people.

Flick a light switch on and you get light. That happens for two reasons. The switch works because it’s linked up to somewhere that generates electricity. You can flick it because every one of your cells has tiny power stations, or mitochondria, creating energy of their own.  

But cancer cells aren’t interested in helping us light up the dark. They focus all their energy on multiplying and growing in places they’re not welcome. That’s not easy, and means cancer cells often need to make energy differently. Around half of all cancers have mutations that change how mitochondria work.  

It’s a trick that tumours use to grow and survive in difficult circumstances, but it might just prove their undoing. Our scientists have found that these mitochondrial mutations make cancers much more likely to respond to immunotherapy treatment.

Understanding immunotherapy

Immunotherapy is one of the most exciting advances in cancer treatment we’ve ever seen, helping more people live with and beyond cancer for longer. It works by reminding our own immune systems how to respond to the disease.  

This might come as a surprise, but our bodies don’t normally need any help.

To first start growing, potential cancers need to find a way around the immune system. They rarely get a chance. Immune cells quickly clear up most changes that could put our bodies in danger. Sometimes, though, a rogue group of cells can trick the rest of the body and find a way to grow without being noticed. That’s when cancer really starts.

Whereas other treatments attack these camouflaged cancer cells directly, immunotherapies point them out to our immune system, giving it the instructions it needs to get back to work. 

Lab Equipment at the Oxford Institute for Radiation Oncology

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But there are still issues. Currently, immunotherapies aren’t able to help everyone. This study builds on a previous paper that found that the drug nivolumab made a difference for just over 1 in 5 people with a form of advanced skin cancer called metastatic melanoma.  

Beating cancer means pushing that proportion higher. It turns out changes to mitochondrial DNA can more than double it.

Finding the flaw in cancer’s camouflage

“We had absolutely no idea that we were going to find this,” says Dr Payam Gammage, a group leader at the Cancer Research UK Scotland Institute. “It’s about as true a discovery as you could ever have.” 

It came in three stages. 

At first, everything was going as planned. The team, which also included scientists from Memorial Sloan Kettering Cancer Centre in the US, engineered their own mitochondrial mutations into cells in the lab and saw how they changed the way cells use energy. 

“It’s still an important finding,” says Gammage, “but it’s what we expected.”  

Then they looked closely at how these changes played out in mouse models. Gammage needs a stronger word than “important” to describe what that showed.  

“We realised that there was this really profound effect happening,” he explains. “Tumours with these mitochondrial mutations activated the immune system, and tumours without these mutations didn’t.” 

Here’s a way to picture that. Powerstations are big, noisy and connected to almost everything. Even masters of disguise like cancer cells can find them hard to camouflage.  

So, when the mice’s immune systems were already suspicious of mitochondrial mutations, immunotherapy gave them the last bit of guidance they needed to start clearing out tumours. Tumours without these mutations were much less likely to respond to treatment. 

Once that was clear, the question shifted to what this might mean for people. Gammage’s team went back to the earlier nivolumab study and re-examined the data according to what they had found.  

In total, the treatment was 2.6 times more effective for people with high levels of mitochondrial DNA mutations. More than 4 in 10 people in this group responded to nivolumab, up from around 2 in 10 in the total trial population.  

Predicting who can benefit from immunotherapy

“There was really no precedent for this at all,” explains Gammage. “And it means you can look at mitochondrial DNA mutations to understand who will benefit from immunotherapy.” 

Today, immunotherapies like nivolumab are often given to people once it’s clear that traditional treatments aren’t working for them. That’s partially because response rates are low and it’s hard to predict who might benefit. Those calculations change when 1 in 5 gets closer to 1 in 2. 

“If you can predict early doors that someone has a good chance of responding to immunotherapy, you can save them years of chemo and radiotherapy,” Gammage continues. With changes to mitochondrial DNA such a common feature of cancer, that means there’s potential to spare many people the side effects of other treatments. 

After years of painstaking lab research funded by Cancer Research UK, we have identified a vital weak spot in cancer. Mitochondrial DNA mutations are a common part of cancer and this amazing discovery has limitless potential.

- Iain Foulkes, executive director of research and innovation at Cancer Research UK

The research team has found the same jump in response rate across multiple different immunotherapies. And they have a plan that could lift it up even higher. 

Making immunotherapy work for more cancers

In the last stage of their study, the researchers started working with a lab-made enzyme called cyto-LbNOX. Adding it to cells makes the immune system think that they have mutated mitochondria. In mice at least, that means cyto-LbNOX can be used to make all tumours more sensitive to immunotherapy.  

If the same thing holds true in humans, cyto-LbNOX could make immunotherapy effective for tumours that don’t currently respond. And, where immunotherapy is already working, adding cyto-LbNOX could make it work better. 

“There’s a lot of hurdles to jump to test this, but if cyto-LbNOX works in humans, we’ll basically have the capacity to make every tumour type sensitive to immunotherapy,” says Gammage. “That means we’re going to be able to treat, and possibly cure, a lot more people. That’s our big vision for the future.” 

You can’t have a vision without light; and for light, you need power. That’s where we come in. Cancer Research Horizons, Cancer Research UK’s innovation arm, is helping Gammage and his team patent their technologies for spotting and mimicking mitochondrial DNA mutations. From there, we’re going to help develop it into potential new treatments.

Tim

Dr Payam Gammage

Group leader at the CRUK Scotland Institute

Dr Payam A. Gammage is a member of the faculty at the CRUK Scotland Institute, University of Glasgow, where he leads the Mitochondrial Oncogenetics laboratory. He holds MSci and PhD degrees in Neuroscience and Biochemistry from University College London and the University of Cambridge, and is the recipient of major awards from the European Research Council and the National Cancer Institute in the US. He was also recently elected to membership of the prestigious European Molecular Biology Organisation (EMBO) Young Investigator Programme. Dr Gammage’s research focuses on the reasons mitochondrial DNA changes in cancer, and what those changes mean for people with the disease.

Mahmood, M., Liu, E.M., Shergold, A.L. et al. Mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade response in melanoma. Nat Cancer (2024). https://doi.org/10.1038/s43018-023-00721-w  

    Comments

  • Gary waters
    16 February 2024

    I am currently on Nivoblumab it has being a game changer for me but unfortunately it doesn’t work on every one at the moment. Reading this gives me hope for other people

  • Pauline Mitchell
    14 February 2024

    Sound like a fantastic discovery for cancer and treatment for it. Especially if the cancer can be found much sooner. Immunotherapy to help your own body fight the mutations is amazing discovery. Thank you for putting so much work into fighting cancer maybe won’t help me in my lifetime but hopefully my family and grandchildren. Millions of people could survive and millions could have a much longer survival rate. Well done everyone involved with this breakthrough 😍😍😍

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Read our comment policy.

    Comments

  • Gary waters
    16 February 2024

    I am currently on Nivoblumab it has being a game changer for me but unfortunately it doesn’t work on every one at the moment. Reading this gives me hope for other people

  • Pauline Mitchell
    14 February 2024

    Sound like a fantastic discovery for cancer and treatment for it. Especially if the cancer can be found much sooner. Immunotherapy to help your own body fight the mutations is amazing discovery. Thank you for putting so much work into fighting cancer maybe won’t help me in my lifetime but hopefully my family and grandchildren. Millions of people could survive and millions could have a much longer survival rate. Well done everyone involved with this breakthrough 😍😍😍

Tell us what you think

Leave a Reply

Your email address will not be published. Required fields are marked *

Read our comment policy.