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Gut Microbiome May Identify Cancer Patients Who Will Respond to Immunotherapy

Computer-generated image of cancer cells.
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A signature of bacterial strains in the gut microbiome may be able to identify cancer patients that will respond well to certain immunotherapy drug combinations, according to a new study from Wellcome Sanger Institute and Olivia Newton-John Cancer Research Institute researchers.

The study is published in Nature Medicine.

Cancer immunotherapies don’t work for everyone

Immunotherapies have been a fantastic innovation for cancer treatment. They work by helping to restore the immune system’s ability to recognize and kill cancer cells, which commonly find ways to escape the immune system.

Numerous cancer immunotherapies have come onto the market, including immune checkpoint inhibitors. However, a major stumbling block for these therapies is that they are not effective in all patients, and it is difficult to predict these patients in advance.

This means that some patients receive unnecessary treatments that do not benefit their treatment and can potentially cause multiple side effects.

Nonetheless, approved biomarkers to predict responses to immune checkpoint inhibitors still have their limitations. To find other avenues for prediction, studies have investigated whether differences in the gut microbiome – the collection of microorganisms that reside in our guts – could be tied to immunotherapy responses.

“The last five years have seen a surge in interest in the relationship between gut microbiota and cancer response to immune checkpoint blockade (ICB),” Dr. Ashray Gunjur, lead author of the study and a clinical research training fellow at the Wellcome Sanger Institute, told Technology Networks. “However, a key challenge has been the lack of consistency in microbiota associated with ICB response or non-response across cohorts.”

Gunjur and colleagues therefore investigated if a more granular approach focusing on the bacterial strain – rather than the species or genus – could yield better results, and if there was consistency across cancer types.

What is an organism strain?

A strain is a subgroup of organisms that belong to the same species, but have characteristics not shared by other members of the same species. Bacteria – and other microorganisms and infectious agents such as fungi and viruses – can have many strains within a single species.

Creating a microbiome “signature” for ICB response

Gunjur and colleagues analyzed stool samples from 106 patients – with a variety of different cancer types – who took part in a clinical trial testing ICB drug combinations. Deep shotgun metagenomic sequencing of stool samples was used to map the bacteria in their gut microbiomes, narrowing them down to their particular strain.

Multiple strains were identified in the microbiomes of people who had good responses to ICB treatments, allowing the researchers to build a microbiome “signature” found in patients who responded well.

They then trained a machine learning model to recognize this signature and predict patients that would respond to combination ICB therapy. The model was able to recognize responders across different cancer types – including melanoma – as well as in patients across different countries.

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Nevertheless, the model was not effective at predicting responses for patients who received only one ICB drug targeting programmed cell death protein 1 (PD-1). It was only effective at predicting responses to combination ICB therapy.

This suggests that the relationship between gut microbiome and treatment response is specific for particular drug combinations, and that similar studies should focus on tailoring the analysis to the immunotherapy combination, regardless of cancer type.

“Overall, this work provides further support for the role gut microbiota play in modulating anti-cancer immune response,” said Gunjur.

Further work into microbiomes and ICB responses

“This study was observational and exploratory, so we cannot comment on the direction of causality of the associations between microbial abundances and response,” Gunjur explained, highlighting some limitations to the study. “The lack of longitudinal stool sampling precluded any analysis of temporal changes in the gut microbiome as a result of ICB therapy.”

“We believe a key next step is to better understand how strain-variation of key species highlighted in this study affects host immunity and ultimately anti-cancer immune responses,” he added. “As such, we are curating a collection of strains from these key species, isolated from patients or healthy participants, to better define intra-species variation in functions, metabolism and interactions with host or cancer cells.”

Reference: Gunjur A, Shao Y, Rozday T, et al. A gut microbial signature for combination immune checkpoint blockade across cancer types. Nat Med. 2024:1-13. doi: 10.1038/s41591-024-02823-z

Dr. Ashray Gunjur was speaking to Dr. Sarah Whelan, Science Writer for Technology Networks.

About the interviewee:

Dr. Ashray Gunjur is a clinical research training fellow at the Wellcome Sanger Institute, where he is undertaking a clinical PhD. His research focuses on the gut microbiome and predictive biomarkers for immune checkpoint blockade responses and toxicity. Ashray is also a qualified medical oncologist and received his MBBS (Hons) from the University of Melbourne in 2012.