How Gut Bacteria Shape the Battle Against Skin Cancer: Written Lay Summary

How Gut Bacteria Shape the Battle Against Skin Cancer

Cancer is a formidable and pervasive disease, and the treatment can often be worse than the disease. That holds true for melanoma (skin cancer). Many people are treated with single or combination Immune Checkpoint Inhibitor (ICI) therapy. ICIs are medicines that help your immune system fight cancer. They work by blocking certain “checkpoint” signals and tell your immune system to recognize and destroy cancer cells.

Though unfortunately, less than 50% of people get better from single ICI treatment, and combination treatments (i.e. two or more ICIs) can have highly toxic side effects. So, scientists are constantly testing these treatments to check if they are safe and effective.

This is the story of what might help people with 4th stage melanoma (cancer that has spread to other parts of the body) respond well to ICIs and recover. One such thing is the gut bacteria (in the intestine). The question is can the colony of bacteria in the gut (gut microbiome) speed-up the response to ICI? And if so, should this be an important target for future treatment?

So, what did the researchers do?

Dr. Karla Lee and her colleagues from King’s College London in UK, along with researchers at international universities, looked at 5 groups of adults aged 19 to 94 years old from UK, the Netherlands and Spain. All men and women had advanced stage 3 or 4 melanoma that couldn’t be operated and had not yet received ICI therapy. The biggest groups were from UK and Netherlands (55 people each). They analysed 165 stool samples of these people and data from 147 previously published studies using metagenomic sequencing. This is a tool that shows types of gut bacteria and what they do. These groups were then given single and combination ICI therapies, and scientists looked at the response to treatment. Two measures were taken and compared: how many responded to ICI at 6 months and how many people had no cancer progression at 12 months.

Here’s what they found…

People’s gut bacteria seem to influence their response to single and combined ICI therapies. The type of bacteria varies based on people live, their diet, how samples were collected and processed. So, pattern of bacteria in those who respond to ICI and those who don’t, changes completely from one group to another. For instance, people from UK and Netherlands differed in how many had taken other treatment for cancer previously. They also showed completely different bacteria signalling patterns that helps ICI become effective. This means that no single test can say whether a patient will respond to ICIs.

A shift of gears!

They decided to use a machine-learning approach called Lasso to do a deeper dive, to see which bacteria patterns best matched treatment response. Lasso analysed the bacteria patterns and their functions; to identify the types of bacteria that significantly predict who is likely to benefit from ICIs. The answer was again different according to groups. A way of calculating this difference is using the Area Under the Curve – Receiver Operating Characteristic (AUC-ROC). This calculation (when done many times) tells the differences between those who responded well to treatment those who didn’t. AUC-ROC’s perfect score is 1 and 0.50 is the same as guessing. The UK group had a strong score of 0.78 – while Netherlands was only 0.53.

A change of goalpost to progression-free survival at 12 months

When looking at progression-free survival at 12 months, the AUC-ROC score flipped again where people from the Netherlands – 0.64 and UK – 0.57. The researchers found that if you train Lasso on what predicts recovery from skin cancer for the UK group it doesn’t give a usable result for Netherlands. Where people live had about ten times more impact on their gut bacteria than things like age or weight and use of antacids. So, this cannot predict ICI response.

A move away from groups of people to bacteria-types

Again, no single bacteria emerged as a reliable predictor of people’s response to treatment. But a cluster of microbes seemed to be important:

• For responders: Those that seem to help healthy gut and heart health were Roseburia spp., while others that promote digestion produce Butyrate. Akkermansia muciniphila, Phascolarctobacterium succinatutens and Lactobacillus vaginalis were linked to both the response rate to ICIs at 6 months and progression-free survival at 12 months.

• Non-responders: Bacteroides clarus, showed up a lot in people from the UK. These people also had high level of side effects and toxicity from ICIs. Another bacteria Ruminococcus gnavus was present, in previous studies linked to unhealthy heart and metabolism (cardiometabolic health) and conditions where the body’s immune system attacks itself (auto-immune problems).

Next, looking at the jobs these bacteria do…

Two ways gut bacteria work were found in responders to treatment:

• Forming a protective film, or “pellicle,” which helps bacteria stick together and communicate. This process involves an enzyme called glycosyltransferase, found in bacteria such as Intestinimonas butyriciproducens and Bifidobacterium species.

• Enzymes called DNA adenine methylases, which add tiny chemical tags to certain genes to switch them on, helping the immune system work better.

In non-responders to treatment:

• Disease agents like Rumminococcus torques and Escherichia coli; help transport a chemical that consumes sugars/carbohydrates and are not good for health.

The big question remained – do these bacteria cause the response to treatment or do they just happen to change at the same time?
A big concern – do common antacids impact the gut colonies?

A lot of people use antacid medication, which reduces stomach acid and changes the gut bacteria. Earlier studies showed a negative effect on response to ICI treatment. However, this study did not show any impact on the response to ICI either in the response rate to ICIs at 6 months and progression-free survival at 12 months.

They found that those patients that did well on ICI also had a favourable gut microbiome.

To sum up…

These findings suggest that the gut microbiome could help explain why some people respond better to immunotherapies like ICIs. Recognizing which bacteria and what they do to support recovery could lead to more personalised cancer treatments. Exactly how seems to be a bit more complicated. No single test can predict response to treatment; because gut bacteria colonies are shaped by where you come from.
Future studies should focus on studying specific strains of bacteria, the jobs they do and what they produce and not just list them. Each person’s gut is unique. Instead of relying on stool samples only, looking at how gut lining reacts to the bacteria may personalize treatment. For accuracy, scientists will need to look at data from large numbers of people.

Image: “Wild garden of the gut bacteria 2” by Nicola Fawcett is licensed under CC BY-SA 4.0.