Researchers at NYU Langone Health’s Perlmutter Cancer Center have found that patterns in the populations of bacteria in the gut microbiome can predict which melanoma patients are more likely to benefit from immunotherapy. The study, published in Cell, showed that specific bacterial signatures, when analyzed in the context of a patient’s overall microbiome profile, can forecast cancer recurrence after immune checkpoint blockade (ICB) with accuracy as high as 94%. The findings suggest that using this information could help identify which patients will respond to ICB treatment and which are more likely to relapse.
“Our study identified for the first time gut bacterial types that can serve as markers of increased recurrence risk in these specific patients, which will help to tailor treatment,” said study senior author Jiyoung Ahn, PhD, a professor of population health at NYU Grossman School of Medicine and associate director of population research at NYU Langone’s Perlmutter Cancer Center.
ICB is a form of cancer treatment that enhances the immune system’s ability to recognize and attack tumor cells. Drugs such as nivolumab and ipilimumab work by inhibiting molecular “checkpoints” that normally restrain T cell activity to allow immune cells to mount an anti-tumor response. Because of the success of ICBs in advanced cancer, this form of treatment is now expanding into earlier-stage, higher-risk patients following surgery.
“Immune checkpoint blockade (ICB) therapy has transformed the management of advanced, unresectable melanoma,” the researchers wrote. However, it is not effective for all patients. “Clinical benefit remains unpredictable, with approximately 25%–40% of patients experiencing disease recurrence despite therapy,” they added.
In their search for biomarkers that could stratify responders from non-responders, the NYU investigators analyzed stool samples from 674 melanoma patients enrolled in the Phase III CheckMate 915 clinical trial. Participants had undergone surgical tumor removal and then received either a combination of nivolumab plus ipilimumab or nivolumab alone for up to one year. Using shotgun metagenomic sequencing, the researchers characterized the gut microbiome at strain-level resolution before treatment and, in a subset of the patients, during therapy.
Their analysis identified bacterial taxa, including Eubacterium, Ruminococcus, Firmicutes, and Clostridium, that were associated with recurrence risk.
An important finding was that predictive accuracy was dependent on matching patients by their overall microbiome composition. “Recurrence prediction was strongest when the validation cohort exhibited GMB profiles similar to those in the discovery cohort,” the researchers wrote. When patients were closely matched based on microbial similarity, prediction performance reached area under the curve (AUC) values between 0.78 and 0.94. “This evidence indicates that taxonomic markers for prediction of recurrence are generalizable across regions for individuals with similar GMB composition,” the researchers noted.
The study’s design sought to address a longstanding challenge in microbiome research, notably that earlier studies had shown bacterial markers linked to immunotherapy response varied widely by geography.
“Past studies have struggled because the gut bacteria that predict treatment success seemed to change from one region to another,” Ahn said. “Our study provides a new method that overcomes this barrier, showing that these markers are indeed generalizable if we account for the person’s underlying microbiome.”
The study also showed that the gut microbiome remains stable during treatment, a finding that suggests the potential to manipulate the gut microbiome before therapy begins. “This stability suggests an important window of opportunity before treatment begins,” Ahn told Inside Precision Medicine. “We are currently planning diet-based intervention trials aimed at actively modifying the microbiome prior to immunotherapy. The goal is to move beyond observational associations toward actionable strategies that can improve treatment response.”
The biological mechanisms underlying these associations may relate to how gut bacteria influence immune activity. “These taxa are largely fiber-metabolizing bacteria that produce short-chain fatty acids, such as butyrate,” Ahn said. “These metabolites are known to play important roles in modulating immune function, including enhancing anti-tumor immune responses and regulating inflammation.” The researchers also noted links between these bacteria and metabolic pathways such as “glycolysis/gluconeogenesis” and the “pentose phosphate pathway,” which prior research has shown can affect cancer treatment outcomes.
Evidence supporting the microbiome’s role in immunotherapy response has been accumulating. Prior studies in metastatic melanoma have shown that fecal microbiota transplantation can restore responsiveness to ICB in some patients, via activation of CD8+ T cells. But earlier research has been limited by small sample sizes and regional variability.
The current study, however, examines the influence of the microbiome during adjuvant therapy and provides a potential method for overcoming geographic differences.
“The main challenge is that prediction models may be limited to subsets of populations with similar underlying microbiome structures,” Ahn noted. “Moving forward, we will need well-characterized, large-scale microbiome reference datasets that allow appropriate matching across populations and regions.”
Additional work is needed in order to use these signatures in the clinic. “The next steps include validation in independent cohorts and prospective trials,” Ahn noted. “Ultimately, these biomarkers have the potential to guide patient stratification and optimize immunotherapy outcomes in clinical settings.”
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