Having the right balance between good and bad microbes in the gut may improve the likelihood that immunotherapy successfully treats melanoma, which is the most aggressive and dangerous form of skin cancer.

This was the conclusion that researchers from the University of Chicago, IL, came to after they found much higher levels of specific bacteria in the stool samples of people with melanoma who responded to immunotherapy, compared with those who did not respond to the treatment.

Among the "good" gut bacteria that the team found to be abundant in those individuals who responded to "PD-1 blockade" immunotherapy were Enterococcus faecium, Bifidobacterium longum, and Collinsella aerofaciens.

The scientists found that having higher levels of these strains of bacteria in the gut seemed to increase penetration of immune system T cells into the microenvironment of tumors and boost their ability to kill cancer cells.

In the journal Science, they note how the people who did not respond to the immunotherapy also had an "imbalance in gut flora composition, which correlated with impaired immune cell activity."

'Link is strong enough to be causal'

Prof. Thomas Gajewski, who directed the study, says that the link between the specific gut bacteria and the clinical response to the immunotherapy was so strong that it indicates "a causal relationship."

"Specific bacteria clearly contribute to improved anti-tumor immunity in patients," he explains, and adds, "The gut microbiota has a more profound effect than we previously imagined."

Melanoma is a type of skin cancer that starts in melanocytes, which are a type of cell found in the epidermis, or the outer layer of skin.

Melanoma is much more aggressive than most other skin cancers, and it tends to spread to other tissues, or metastasizes, if not found early. Though melanoma only accounts for 2% of all cases, it causes the most deaths from skin cancer.

Estimates suggest that 87,110 people in the United States discovered that they had melanoma in 2017, accounting for 5.2% of all new cases of cancer. The vast majority (92%) of melanoma patients survive for 5 years or longer after diagnosis.

Cancer hides from the immune system

Immunotherapy is a relatively new approach to the treatment of cancer, and it aims to unblock or ramp up the immune system's natural ability to find and kill cancer cells.

Cancer arises when normal cells malfunction and then start to grow out of control. In the case of melanoma, the trigger can be damage to cellular DNA caused by exposure to ultraviolet (UV) radiation. It is thought that around 65% of melanoma cases arise from UV exposure.

The body has built-in mechanisms to deal with faulty cells. One of these is that faulty cells display signals that are picked up by patrolling cells of the immune system, which then targets and eliminates the rogue cells.

But that does not mark the end of the story, because the immune system is also hardwired with mechanisms called immune checkpoint pathways, which stop the response being too strong and causing collateral damage to normal cells.

However, cancer cells are able to exploit these immune checkpoint pathways in order to stop the immune system from seeing them. But one approach, called anti-PD-1 immunotherapy, aims to block the cancer cells' ability to use one of the immune checkpoint pathways.

Immunotherapy doesn't work for everyone

However, as the researchers note in their paper, despite its "major impact on cancer treatment," anti-PD-1 immunotherapy "has only benefited a subset of patients."

In previous work on mice, Prof. Gajewski and his team had already established that there was a link between specific gut bacteria and potency of immunotherapy.

For the new study, the scientists tested stool samples from 42 people before they underwent immunotherapy for metastatic melanoma. They used three different methods to analyze and identify the gut microbes in the stool samples.

Most of the patients (38) were treated with anti-PD-1 drugs such as nivolumab or pembrolizumab. The remaining patients (4) were treated with a related drug called ipilimumab, which is an anti-CTLA4.

The results showed that the patients who responded to their immunotherapy had higher levels of eight species of bacteria—the "good" bacteria—in their stools.

Also, the people who did not respond to the treatment had higher levels of two species of bacteria—the "bad" bacteria. Those who had a higher ratio of good to bad bacteria all responded to the treatment, and their tumors shrank.

Good gut bacteria boosted immunotherapy

The researchers then ran an experiment wherein they transferred gut bacteria from the patients into the guts of germ-free mice and then transplanted melanoma tumors into the mice 2 weeks later.

The tumors grew more slowly in two of the three mice that received gut bacteria from the people who had responded to the immunotherapy.

In the three mice that received gut bacteria from the non-responding patients, only one of them showed signs of slow tumor growth, while the other two had fast-growing tumors.

In addition, the team found that anti-PD-1 treatment only worked in mice that received gut bacteria from the responding patients.

The researchers are already moving forward with the work. They now want to test whether or not probiotics might boost immunotherapy and are planning a clinical trial using Bifidobacteria.

They also want to produce a longer list of the gut bacteria that help and hinder cancer patients and work out how the microbes interact with the immune system's ability to control cancer.

"Our results strongly suggest that the microbiota is a major factor, a gatekeeper for the immune response against a tumor. Without microbial support, the immune response just never quite gets going."

Prof. Thomas Gajewski