▎ WuXi AppTec content team editor
The advent of immunotherapy has completely changed the treatment pattern of many cancers. Extremely aggressive malignant tumors, such as advanced melanoma, which were originally incurable terminal diseases, can now be controlled for a long time, and the lives of many patients have been greatly extended.
Unfortunately, however, not all patients benefit from immunotherapy. Also taking melanoma as an example, less than half of patients currently respond positively to immune checkpoint inhibitors, and for the remaining patients, the effect of immunotherapy is very limited, and some patients do not even respond at all.
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A growing body of evidence suggests that patient responses to cancer immunotherapy may be linked to an important factor: the gut microbiota that varies from person to person.
Everyone's gut is home to more than 10 trillion bacteria, viruses, fungi, and other microbes, whose composition is influenced by host genetic factors or can be altered by diet, probiotics, antibiotics, or fecal transplantation. At the same time, the intestinal microbiome is the regulator of the immune system, and when the intestinal flora changes, it will also affect the role of the human immune system.
Recently, the journal Nature Medicine launched two papers at the same time, pointing out that melanoma patients have complex interactions between cancer immunotherapy responses and the gut microbiome, which may have important guiding significance for developing better immunotherapy strategies in the future.
The first study noted that "harmful" gut bacteria may have a greater impact than beneficial bacteria in melanoma patients who receive immunotherapy.
The researchers analyzed the composition of the patient's gut microbiota prior to treatment versus clinical outcomes after treatment with anti-PD-1 inhibitors, and used computer modeling techniques to determine which bacteria were associated with a better treatment response or a worse treatment response.
Bioinformatics analysis showed that about a year after the start of treatment, the gut microbiota became the dominant factor in the response to treatment, and that the microbes that hindered treatment appeared to play a greater role than the microbes that enhanced the treatment.
They found that the bacteria associated with the favorable response were limited to species of Actinobacteria and Firmicutes, the family Officicetes, and Rumenaceae, while Gram-negative bacteria were associated with inflammatory host intestinal genetic characteristics, an increased ratio of blood neutrophils to lymphocytes, and adverse outcomes.
In another study, an international team of researchers recruited hundreds of patients with advanced melanoma from five cohorts in the UK, the Netherlands and Spain to determine the association of gut microbiota traits with immunotherapy responses through large-scale metagenomic analysis.
The researchers examined stool samples from patients before they were treated with immune checkpoint inhibitors, sequencing their gut microbiomes. Subsequently, the association between the patient's gut microbiome and their overall response rate (ORRs) and progression-free survival (PFS) to immunotherapy was analyzed through machine learning.
The findings suggest that the role of the human gut microbiome in immunotherapy responses appears to be more complex than previously thought. Because they observed that different cohorts involved different bacterial species. Although the identification of the presence of three bacteria (Bifidobacterium pseudocatenulatum, Roseburia spp., and Akkermansia muciniphila) appeared to be associated with a more aggressive immune response, none of the microbial species could act as biomarkers that were perfectly consistent in all cohorts.
The results of the analysis also showed that the intestinal flora itself was strongly influenced by factors such as the patient's constitution, drug use (e.g., proton pump inhibitors that inhibit gastric acid secretion, antibiotics), and dietary patterns (e.g., plant-based diet, Mediterranean diet), which also affected the association between the intestinal flora and the clinical immune response.
"Between subgroups, patients based on healthy gut flora nearly doubled their survival rates." Professor Tim Spector, one of the study leaders at King's College London, said: "This study highlights the potential impact of good diet and gut health on survival chances for patients receiving immunotherapy. ”
Although this is already the largest study of its kind, the researchers point out that due to the different properties of the gut microbiome, there is a need for larger studies to find out which characteristics of the gut microbiome are more likely to directly affect the positive response to immunotherapy, so as to develop new personalized therapies.