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Gut Microbes May Contribute to Immunotherapy Response

NEW YORK (GenomeWeb) – Independent research teams have identified gut microbial community features that appear to coincide with more favorable responses to checkpoint blockade immunotherapy targeting PD-1.

For one of the two studies, both published online today in Science, a team from France, the US, and Sweden looked for potential ties between gut microbiome features and anti-PD-1 immune checkpoint blockade response in 100 individuals with renal cell carcinoma or non-small cell lung cancer.

The work followed from the team's preliminary experiments suggesting antibiotic treatment curbed anti-PD-1 and/or anti-CTLA-4 treatment effectiveness in mouse models of sarcoma and melanoma. Likewise, checkpoint blockade response patterns for 249 individuals with lung, kidney, or urothelial cancers pointed to diminished response and poorer survival outcomes for the 69 patients with recent antibiotic prescriptions.

When they used quantitative metagenomic shotgun sequencing to directly measure gut microbes at diagnosis and over the course of treatment in 60 individuals with non-small cell lung cancer and 40 renal cell carcinoma patients, the researchers saw a more robust response to anti-PD-1 treatment in those with enhanced microbial species richness.

That team highlighted one species in particular — Akkermansia muciniphila — that was significantly more common in lung or kidney cancer patients with better checkpoint blockade outcomes. That bug turned up in 11 of 16 individuals showing partial response to checkpoint blockade treatment and in 23 of the 40 individuals with stable disease. In contrast, A. muciniphila only turned up in gut communities from about one-third of non-responders.

Consistent with the proposed role for gut microbiota in influencing immune response to cancer following anti-PD-1 therapy, the investigators were able to boost response to such treatment by transplanting fecal microbes from responder patients into germ-free mice or mice treated with antibiotics — an effect that could only be achieved with fecal transplants from non-responders that were supplemented with response-associated bugs such as A. muciniphila.

Though questions remain regarding potential mechanisms, the authors noted that the findings so far "suggest that the microbiome governs the cancer-immune set point of cancer-bearing individuals and offer novel avenues for manipulation the gut ecosystem to circumvent primary resistance to [immune checkpoint inhibitors]."

For the second study, researchers from the University of Texas MD Anderson Cancer Center and their colleagues used 16S ribosomal RNA sequencing to compare gut and/or oral microbe community membership in 112 metastatic melanoma patients who did or did not respond to anti-PD-1 treatment.

In fecal samples from 30 responders and 13 non-responders, for example, the team found that response to the immune checkpoint blockade drugs was associated with enhanced microbial diversity in the gut. On the other hand, the researchers didn't find any diversity differences in oral samples from 54 individuals who responded to anti-PD-1 treatment and 32 who did not.

Using metagenomic sequencing, the team delved further into the apparent gut microbiome association with response — an analysis that suggested ties between better anti-PD-1 response, longer progression-free survival times, and enhanced levels of Faecalibacterium and other bacteria in the gut. On the other hand, Bacteroidales bacteria tended to be more common in the guts of metastatic melanoma patients with poorer checkpoint blockade response.

Again, mouse experiments indicated that fecal transplants from treatment responders promoted a microbiome environment in the mouse gut that diminished tumor growth in response to PD-1-targeting treatment.

Based on their follow-up experiments, including mass cytometry-based analyses of the tumor microenvironment in mice, the authors of that study suggested that "patients with a 'favorable' gut microbiome … have enhanced systemic and anti-tumor immune responses mediated by increased antigen presentation, and improved effector T cell function in the periphery and the tumor microenvironment."

The study's co-senior author Jennifer Wargo, a surgical oncology and genomic medicine researcher at the University of Texas MD Anderson Cancer Center and cofounder of the cancer immunotherapy-focused microbiome-profiling firm MicrobiomeDX, presented oral and gut microbiome findings for more than 100 anti-PD-1-treated metastatic melanoma patients at this year's American Society of Clinical Oncology meeting. 

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