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Cancer Immunotherapy Response Linked to Gut Microbes in Multiomic Analysis

NEW YORK – New research suggests pan-cancer responses to immunotherapy may be influenced by an individual's gut microbial community members and metabolites produced by those gut bugs.

The work "highlights significant advances in understanding the role of the gut microbiome in modulating the efficacy of anti-PD-1/PD-L1 immunotherapy," Haoyan Chen, a researcher affiliated with the Shanghai Jiao Tong University's Shanghai Cancer Institute and the Shanghai Institute of Digestive Disease who led the project, said in an email.

For their study, published in Cell Metabolism on Tuesday, Chen and his colleagues used metagenomic sequencing to characterize fecal microbiome patterns in stool samples from 165 solid tumor patients being treated with anti-PD-1 or anti-PD-L1 immune checkpoint blockade therapy. They also incorporated tandem mass spectrometry-based stool metabolomic data for 156 participants, along with follow-up single-cell RNA sequencing data on tumor samples from mouse models.

"While earlier research has suggested that the gut microbiome can influence immunotherapy responses, our study takes a deeper, multiomics approach to identify distinct microbial signatures associated with treatment outcomes across different cancer types," Chen explained.

By comparing microbial sequence and metabolic data from immunotherapy responders with those from individuals with limited treatment responses, the team was able to track down signatures for immune checkpoint blockade treatment response, highlighting five response-related enterotypes marked by microbes from the Ruminococcus, Escherichia, Bacteroides, Clostridium, or Prevotella genera, respectively.

"These enterotypes were not only associated with distinct bacterial compositions but also had unique metabolic signatures," Chen said, adding that these and other findings from the study point to the possibility of profiling gut microbial communities for clues to immunotherapy response.

After validating the gut microbiome and metabolome ties to immunotherapy response using data for another 138 cancer patients, along with published microbial metagenomic data for 568 cancer patients, the investigators focused in on a microbial metabolite known as phenylacetylglutamine (PAGln) that appeared to be particularly associated with reduced response to anti-PD-1 immunotherapy.

"Our study found that PAGln negatively affects the immune response to anti-PD-1 therapy by inhibiting T-cell activation," Chen said. "This underscores the critical role that microbial metabolites like PAGln play in modulating immune responses and potentially contributing to resistance to immunotherapy."

Together, the authors explained, the results revealed "interplay among the gut microbiome, the gut metabolome, and immunotherapy response, identifying potential biomarkers to improve treatment outcomes."

When they used the multiomic data to put together immunotherapy response signatures, the researchers found that a signature based on nine microbial metabolites showed promise for predicting immunotherapy response in a set of 733 cancer patients, including study participants and individuals profiled for four prior studies. The predictive performance was further improved using a signature based on a dozen gut microbial representatives and three microbial metabolites.

"The signature-based models demonstrated promising accuracy in predicting treatment response," the authors wrote, adding that the current results "have the potential to guide clinical decision-making in cancer immunotherapy."

More broadly, Chen suggested that the findings may ultimately lead to investigations of microbiome-based interventions such as fecal microbiota transplantation (FMT) that may help shift the gut microbiome toward an immunotherapy response-related state.

"[W]e are continuing to explore FMT as a potential strategy to reprogram the gut microbiome in patients with resistance to anti-PD-1 therapy," Chen said. "In addition, we are investigating other microbial metabolites that may further explain the variations in immune response and contribute to improving cancer immunotherapy outcomes."