Bacteria residing in the gut can stimulate the immune system to launch an assault on cancer cells.
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Boosting Cancer Immunotherapy with Gut Bacteria
New research published in Nature Communications sheds light on our tiny pals residing in our gut, revealing they may hold the key to enhancing cancer immunotherapy treatments.
Immunotherapy, a broad term for treatments that fortify the body's natural defenses against disease, has made significant strides in the cancer world, especially in battling melanoma. One such treatment utilizes drugs dubbed immune checkpoint inhibitors. These little devils block proteins cancer cells produce to shield themselves from immune system attacks.
However, immune checkpoint inhibitors don't always play nice with cancer, and even when they do, they can cause some pretty nasty side effects. So knowing which cancer patients would benefit most from these treatments is crucial.
Gut Microbes and Melanoma
This is where our gut bacteria step into the spotlight. A team led by Sanford Burnham Prebys Medical Discovery Institute in La Jolla, CA, discovered 11 beneficial strains of gut bacteria that team up with the immune system to slow down melanoma's growth in mice.
Further investigation unveiled a signaling pathway called unfolded protein response (UPR) as a major link between these gut bacteria and the immune system's antitumor fighting power. UPR helps maintain protein populations in cells, ensuring they're stable and functioning correctly.
The researchers found that UPR activity was lower in melanoma patients who responded well to immune checkpoint inhibitors, suggesting that UPR activity could serve as a potential marker for selecting patients likely to benefit from this treatment.
Expanding the Impact of Immunotherapy
Melanoma might be rarer than most skin cancers, but it's sneaky. It's more likely to infiltrate nearby tissue and spread to other parts of the body. In the U.S., melanoma accounts for the majority of skin cancer deaths, so finding ways to improve treatment is crucial.
Treatment with immune checkpoint inhibitors has made a dramatic impact on survival rates for melanoma patients, but the cancer still carries a high risk of death once it metastasizes. Even when coupled with other treatments, immune checkpoint therapy only helps about half of all cases. Plus, patients with responsive cancer may still experience autoimmune reactions, limited response duration, and resistance to therapy.
The new study adds to the growing evidence that gut microbes can influence the effectiveness of immunotherapy. Prior research has shown that certain gut bacteria strains can boost the efficacy of treatments, while specific antibiotics and probiotics can reduce it.
The Mouse Model Conundrum
For their investigation, the researchers used mice that lacked the RING finger protein 5 (RNF5), which aids in removing misfolded proteins. They found that these mice could halt melanoma tumor growth as long as their immune systems and gut microbe populations stayed healthy. But if they housed the RNF5-lacking mice with mice that had the protein, or treated them with antibiotics, the animals lost their ability to fight melanoma tumors. This shows that gut microbes play a crucial role in immune defenses against melanoma.
Further investigation revealed the involvement of various immune system components in the gut and the reduction in UPR activity in immune and gut cells was enough to activate immune cells. When the researchers transferred the 11 beneficial bacterial strains to germ-free mice without gut bacteria, it triggered an antitumor response and reduced melanoma tumor growth.
Lastly, the team confirmed the results in tissue samples from three separate groups of melanoma patients who later received immune checkpoint inhibitor treatment. The correlation between response to treatment and UPR component levels suggests that these could serve as potential biomarkers to predict who would benefit most from immunotherapy.
What's Next for Immunotherapy?
The team plans to identify the antitumor molecules that gut bacteria produce and test their antitumor potency. They also intend to discover which probiotics might enhance their effectiveness in melanoma patients.
In addition, the researchers noted that RNF5-lacking mice were more susceptible to gut inflammation, a side effect that occurs in some checkpoint therapies. They hope to explore this connection further to balance autoimmunity and antitumor immunity, helping more people benefit from immunotherapies.
"Our study establishes a formal link between the microbiome and antitumor immunity and points to the role of the UPR in this process, answering a long-sought question for the field."
Prof. Ze'ev Ronai
- The gut system, in particular beneficial strains of gut bacteria, has been discovered to collaborate with the immune system in slowing down melanoma growth.
- The unfolded protein response (UPR) signaling pathway, identified as a major link between gut bacteria and the immune system's antitumor fighting power, was found to be lower in melanoma patients who responded well to immune checkpoint inhibitors.
- This research adds to the growing evidence that gut microbes can influence the effectiveness of immunotherapy, suggesting that UPR activity could serve as a potential marker for selecting patients who may benefit from immunotherapy.
- The new study indicates that gut microbes play a crucial role in immune defenses against melanoma, and the correlation between response to treatment and UPR component levels could serve as potential biomarkers to predict who would benefit most from immunotherapy.
- The researchers aim to identify the antitumor molecules that gut bacteria produce, test their antitumor potency, and discover which probiotics might enhance their effectiveness in melanoma patients, to further advance health and wellness in cancer treatment.
