Immunotherapy response may be modulated by microbiome

The PRIMM study explored the dynamics of the gut microbiome during immunotherapy treatment. It revealed that longitudinal gut microbiome profiling of advanced cancer patients may provide insights into the pharmaco-microbiomic interactions associated with the increased success of immune checkpoint blockade (ICB).

Immune checkpoint inhibitors (ICIs) were a huge step forward in oncology. They augment T cell-mediated immune responses to tumours, resulting in improved overall survival of cancer patients at advanced stages in certain types of colorectal cancer. However, durable responses are only achieved by a subset of patients. Recent research has shown that the intestinal microbiome might modulate responses to ICIs [1]. Thus, Dr Johannes Björk (University Medical Center Groningen, the Netherlands) set out to analyse longitudinal changes in the gut microbiome in response to ICB treatment, drawing on data from the observational PRIMM study (NCT03643289).

The researchers profiled the gut microbiome of advanced melanoma patients (n=175) undergoing ICB at cancer centres in the UK and the Netherlands. Shotgun metagenomic sequencing was performed on stool samples to compare the microbiome before and during treatment up to 4 times and to explore the correlation with treatment success, measured in terms of 12-month progression-free survival. The researchers used a regression model with higher-order interactions to estimate how bacterial species and metabolic pathways changed in abundance in different (non-)responder strata from baseline to after the final treatment injection. They also disentangled the longitudinal effect of the following treatment characteristics: the use of single (PD-1) or combination (PD-1 and CTLA-4) ICB, prior exposure to antibiotics or proton pump inhibitors (PPIs), and the effect of immune-related adverse events such as colitis.

The results confirmed that some of the previously reported microbial biomarkers at baseline, such as Faecalibacterium prausnitzii and Bifidobacterium longum, also increased longitudinally during treatment. However, these associations were often influenced by concomitant treatment characteristics. For example, microbiota differed between single ICB and combination ICB in patients that took no PPIs and no antibiotics. Compared with non-responders, a higher and increasing abundance of butyrate producers from the Lachnospiraceae family was identified in responders on single ICB over the entire treatment period. “Of course, this is information that we couldn’t have known from previous baseline predictions alone,” Dr Björk pointed out. In contrast, non-response was associated with a higher and increasing abundance of several Bacteroides species, some of which have already been identified in non-responders in previous baseline studies.

Dr Björk also emphasised the effect of confounders like PPI or antibiotic use (see Figure). PPI use was associated with a longitudinal increase in Klebsiella pneumoniae in non-responders that was not seen in non-responders not taking PPIs. Finally, the researchers compared longitudinal microbiota changes in responders who developed colitis compared with those who did not. In general, immunotherapy-induced colitis resembles the gut microbiome in IBD. Bacteriodes caccae was enriched in responders that developed colitis compared with those who did not. Presence of Faecalibacterium prausnitzii, also a butyrate producer, was high and stable in responders resistant to colitis compared with those developing colitis.

Figure: Confounders and outcomes during immunotherapy [2]



PPIs, proton pump inhibitors.

“Microbiome-based interventions should not solely rely on baseline biomarkers. This is key to increasing the efficacy of ICIs. We have to understand the dynamic of the system we want to modulate,” Dr Björk concluded.

1. Hayase E, Jenq RR. Genome Med 2021;13:107.
2. Björk J, et al. Longitudinal changes in the gut microbiome in response to immune checkpoint blockade. OP042, UEG Week 2022, 8–11 October, Vienna, Austria.

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Posted on 2 December, 202223 April, 2024