Intestinal microbes triggering immune system response against cancer cells.
A global study has unveiled gut bacteria that can bolster the immune system's might against tumors, paving the way for tailored immunotherapy treatments for cancer patients. This groundbreaking research should help improve and personalize cancer treatments using immune checkpoint inhibitors.
Immunotherapy refers to treatments that boost our immune system's power to combat diseases. One such treatment involves drugs known as immune checkpoint inhibitors. These drugs obstruct proteins produced by cancer cells that protect them from being attacked by immune cells. However, these treatments do not work for all cancer cases, and they can also lead to severe side effects.
This insightful study in Nature Communications may help identify which individuals are most likely to benefit from immune checkpoint inhibitor treatments. The research revolves around the molecular mechanisms that allow gut bacteria to interact with the immune system, thereby impacting its ability to fight cancer.
The Sanford Burnham Prebys Medical Discovery Institute in La Jolla, CA, spearheaded the international team that carried out the research. Collaborations with three hospitals also played a crucial role in the study.
Gut Bacteria, Immune System, and Melanoma
Researchers found 11 strains of gut bacteria that, when interacting with the immune system, helped slow the growth of melanoma tumors in mice. Moreover, they zeroed in on a signaling pathway known as the unfolded protein response (UPR) as a key link between gut bacteria and the immune system's antitumor capabilities.
UPR is a crucial cellular process responsible for maintaining protein populations in a stable, healthy state by disposing of those proteins that stress has caused to fold incorrectly. The team discovered lower UPR activity in people with melanoma whose cancer responded to immune checkpoint inhibitors. This finding may indicate UPR activity as a potential marker for selecting melanoma patients more likely to benefit from immune checkpoint therapy.
Enhancing Checkpoint Inhibitor Therapy in Melanoma
Despite the rarity of melanoma compared to most skin cancers, it is the most likely skin cancer to invade nearby tissue and spread to other parts of the body. Because of its propensity to spread, melanoma poses a serious, potentially life-threatening cancer threat.
The American Cancer Society (ACS) estimates that during 2019, around 96,480 people will be diagnosed with melanoma, and 7,230 people will lose their lives to this skin cancer in the United States.
Treatment with immune checkpoint inhibitors has greatly improved survival rates for people with melanoma. However, the cancer still carries a high risk of causing death once it spreads, even when doctors combine immune checkpoint therapy with other treatments. In approximately half of all cases, such combined treatment only benefits the cancer, and individuals with responsive cancer may still experience autoimmune reactions, limited response duration, and resistance to therapy.
The recent study adds to the growing evidence that gut microbes play a significant role in the effectiveness of immunotherapy for melanoma. Earlier research has shown that some strains of gut bacteria can increase treatment effectiveness, while certain antibiotics and probiotics can reduce it.
An Effective Mouse Model
For their investigation, the researchers used mice that lacked RING finger protein 5 (RNF5), which helps cells remove incorrectly folded proteins. These mice were able to halt melanoma tumor growth as long as their immune systems and gut microbe populations remained healthy. However, if they housed RNF5-lacking mice with mice that did have the protein, or if they treated them with antibiotics, the animals lost their ability to fight melanoma tumors. This revealed the crucial role of gut microbes in antitumor immune defenses.
Further investigation showed the involvement of several components of the immune system in the gut and the reduction in UPR activity in immune and gut cells that activated immune cells. Using advanced techniques, the team observed that the RNF5-silenced mice contained larger populations of 11 strains of bacteria. When they transplanted these strains to germ-free mice that had no gut bacteria, they triggered an antitumor response and reduced melanoma tumor growth.
In subsequent tests, the team confirmed the results in tissue samples from three separate groups of people with melanoma who received treatment with checkpoint inhibitors. These tests revealed that response to treatment correlated with levels of UPR components, suggesting these could serve as potential biomarkers to predict who would be most likely to benefit from immunotherapy.
The researchers are now determined to identify the antitumor molecules that gut bacteria produce. Once they do, they plan to test the antitumor properties of these molecules and find out which probiotics might increase their effectiveness in individuals with melanoma.
The team also aims to explore another angle: the discovery that RNF5-lacking mice were more susceptible to gut inflammation, a side effect seen in some checkpoint therapies. Perhaps they could utilize this powerful model to figure out how to maintain the balance between 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 study in Nature Communications reveals 11 strains of gut bacteria that can slow the growth of melanoma tumors in mice, enhancing the immune system's capability to fight cancer.
- The unfolded protein response (UPR) is crucial in this process, serving as a key link between gut bacteria and the immune system's antitumor capabilities.
- Lower UPR activity in people with melanoma who respond to immune checkpoint inhibitors might indicate UPR activity as a potential marker for selecting melanoma patients more likely to benefit from immune checkpoint therapy.
- Immunotherapy referencing treatments that boost the immune system's power to combat diseases like cancer, and treatments with immune checkpoint inhibitors are critical in this context.
- One such treatment involves drugs that obstruct proteins produced by cancer cells, thus allowing immune cells to attack them effectively.
- However, these treatments do not work for all cancer cases, and they can possibly lead to severe side effects, highlighting the need for personalized health-and-wellness approaches.
- The research, led by the Sanford Burnham Prebys Medical Discovery Institute, could lead to tailored immunotherapy treatments for cancer patients, improving medical-conditions management.
- Fitness-and-exercise, mental-health, and nutrition are other important factors influencing a person's response to cancer treatments, including immunotherapy.
- The science behind this discovery could pave the way for further exploration into the role of gut microbes in the effectiveness of immunotherapy, potentially revolutionizing the field of health-and-wellness and cancer treatments.
