Melanoma: Why might diet and probiotics aid immunotherapy?

• There is growing interest among cancer patients in using probiotics to improve their health, but it is still unclear how gut microbes alter cancer immunotherapy responses.
• Now, researchers have shown that, in mouse models, the probiotic bacterium, or “good” bacterium, Lactobacillus reuteri travels to melanoma tumors, where it promotes antitumor immunity and facilitates cancer immunotherapy by releasing indole-3-aldehyde (I3A).
• They also found that advanced melanoma patients who responded to immunotherapy had higher I3A levels compared to non-responsive patients.
• More studies are required, but the researchers hope that these findings will pave the way for dietary- and probiotics-based cancer therapy.

In recent years, there has been remarkable progress in the field of cancer immunotherapy. This powerful cancer treatment strategy works by harnessing a person’s own immune system to recognize and destroy cancer cells.

Currently, immunotherapy does not work for everyone. In some patients, tumors shrink or even disappear, while other people do not respond to immunotherapy.

Scientists are trying to figure out why different people have different responses to this form of cancer treatment.

The gut and immunotherapy

One factor that may be responsible for the varying immunotherapy responsiveness is the gut microbiome — or the multitude of microbes found in the gut — which scientists believe may play a role in the body’s anticancer immune response.

Researchers have found that some gut bacteria may modify immune cell activity, whereas others may alter the effectiveness or toxicity of certain drugs.

The gut microbiome varies greatly from person to person. Even though individual humans are about 99.9% identical to one another in terms of DNA, they can be 80–90% different from one another in terms of their gut microbiome.

The gut microbiome can be altered by consuming probiotics, which are found in yogurt, other fermented foods, and dietary supplements.

Now, a new study from the University of Pittsburgh, PA, investigated the effect of probiotics on melanoma immunotherapy response. Its findings appear in the journal Cell.

Dr. Marlies Meisel, senior study author and assistant professor at the University of Pittsburgh’s Department of Immunology, told Medical News Today:

“Cancer patients, including those undergoing immune checkpoint inhibitor (ICI) therapy, are increasingly consuming probiotic bacteria. Probiotics have been found to influence responses to ICI therapy in melanoma. Yet, the mechanisms of how gut probiotics shape systemic tumor immunity and thereby modulate ICI efficacy remain poorly understood. Thus, we set out to test the role of four commonly used probiotic bacteria, including Lactobacillus reuteri.”

What are immune checkpoint inhibitors?

Many cancers stop the body’s immune cells from attacking and killing tumors.

In 2011, the Food and Drug Administration (FDA) approved the use of ipilimumab for the treatment of advanced metastatic melanoma.

Ipilimumab was the first in a class of drugs known as immune checkpoint inhibitors (ICIs), which help the immune system fight cancer by removing the “brakes” that cancer cells put on the body’s natural defenses.

ICIs work by blocking certain proteins, such as CTLA-4, PD-1, and PD-L1, that can stop the body’s cancer-killing T cells. By blocking these proteins, ICIs help the T cells attack and destroy cancer cells.

ICIs have shown promising results in various types of cancer.

Which bacteria may suppress tumors?

To understand how probiotics alter ICI efficacy, the Pittsburgh researchers first had to identify gut bacteria that are capable of suppressing tumor growth.

The researchers orally administered four types of commensal, or “good,” bacteria to mice with melanoma: Bifidobacterium longum, Lactobacillus reuteri, Lactobacillus johnsonii, and Escherichia coli.

They chose these bacteria because they are often used as probiotics and are found in large quantities in the gut microbiome of melanoma patients who respond well to ICI treatment.

The researchers found that giving mice B. longum, E. coli, or L. reuteri on a daily basis, starting one day after implanting B16-F0 subcutaneous tumor cells, effectively slowed down the growth of melanoma and increased survival rates.

L. johnsonii did not have the same effect.

L. reuteri was the most effective in suppressing tumors compared to the other two bacteria and the control group.

The next step was to investigate the mechanism by which L. reuteri limits the growth of melanoma.

How L. reuteri may aid immunotherapy

The researchers found that L. reuteri travels to, colonizes, and persists within melanoma tumors.

At the tumor, L. reuteri metabolizes dietary tryptophan, an essential amino acid found in protein from plant- and animal-based foods, into indole-3-aldehyde (I3A).

I3A activates the aryl hydrocarbon receptor (AhR) within CD8 T cells, which induces interferon-gamma production by these cells.

Interferon-gamma kills tumor cells, either directly or indirectly, which consequently improves the efficacy of cancer immunotherapy with ICIs.

Do the results apply to humans?

The researchers then examined the clinical significance of their mouse model results in a group of patients with advanced melanoma who either had a positive or negative response to ICI therapy.

“Excitingly we found that melanoma patients who responded to ICI had elevated I3A levels in contrast to patients that did not respond,” Dr. Meisel told us.

“Higher levels of I3A before treatment were also associated with a better chance of survival,” she added.

Multiple studies, varying results

Another melanoma mouse model study published in March 2023 also showed a positive correlation between the gut microbiome and cancer immunotherapy efficacy.

The conclusions of that study were that ICI treatment leads to inflammation in the digestive tract, which permits the migration of bacteria from the intestines to lymph nodes close to tumors, where they activate immune cells.

However, a mouse model study of pancreatic cancer published in 2022 produced opposite results, concluding that probiotic bacteria in the gut could undermine immunity in pancreatic cancer.

What are the next research steps?

Dr. Meisel told MNT that their study “provides the rationale to assess the anti-tumor effect of this novel dietary and probiotic combinatorial therapeutic strategy in clinical trials in cancer patients.”

However, more research is needed to determine, first, how many different types of tryptophan-derived AhR ligand-releasing bacteria use this mechanism, and second, whether a diet high in tryptophan leads to more bacteria producing AhR ligands and better immune response in CD8 T cells.

The study authors would also like to go on and investigate how much exogenous, or external, versus endogenous, or internal activation of AhR affects tumor immunity in melanoma, and whether I3A can help patients with other types of ICI-resistant cancers.

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