Gut microbiome affects the response to anti-PD-1 immunotherapy in patients with hepatocellular carcinoma

Abstract

Background Checkpoint-blockade immunotherapy targeting programmed cell death protein 1 (PD-1) has recently shown promising efficacy in hepatocellular carcinoma (HCC). However, the factors affecting and predicting the response to anti-PD-1 immunotherapy in HCC are still unclear. Herein, we report the dynamic variation characteristics and specificities of the gut microbiome during anti-PD-1 immunotherapy in HCC using metagenomic sequencing. Results Fecal samples from patients responding to immunotherapy showed higher taxa richness and more gene counts than those of non-responders. For dynamic analysis during anti-PD-1 immunotherapy, the dissimilarity of beta diversity became prominent across patients as early as Week 6. In non-responders, Proteobacteria increased from Week 3, and became predominant at Week 12. Twenty responder-enriched species, including Akkermansia muciniphila and Ruminococcaceae spp., were further identified. The related functional genes and metabolic pathway analysis, such as carbohydrate metabolism and methanogenesis, verified the potential bioactivities of responder-enriched species. Conclusions Gut microbiome may have a critical impact on the responses of HCC patients treated with anti-PD-1 immunotherapy. The dynamic variation characteristics of the gut microbiome may provide early predictions of the outcomes of immunotherapy in HCC, which is critical for disease-monitoring and treatment decision-making. Electronic supplementary material The online version of this article (10.1186/s40425-019-0650-9) contains supplementary material, which is available to authorized users.

Immune-based therapies for hepatocellular carcinoma

“…The liver does not harbour a known intrinsic microbiome but the gut microbiota plays a critical role in liver inflammation, chronic fibrosis, liver cirrhosis and HCC development via the gut-liver axis [168][169][170]. A pilot study of 8 HCC patients treated with PD-1 inhibitors has revealed taxonomic diversity and enrichment in 20 species including Akkermansia and Ruminococcaceae to predict for response [171] suggesting characteristic alterations in the gut microbiota profile to have potential as predictive biomarkers of clinical benefit in ICPIrecipients. The precise molecular mechanisms that may facilitate anti-tumour immunity warrant further elucidation in larger cohorts.…”

The Bacterium Akkermansia muciniphila: A Sentinel for Gut Permeability and Its Relevance to HIV-Related Inflammation

“…Remarkably, the influence of the gut microbiota composition in modulating tumor responses to immunotherapy has also been reported in various cancers such as melanoma, lung and kidney cancer. This effect was observed in different geographic regions where microbiota might differ (North America, Europe, East Asia) (4,(73)(74)(75). Reconstitution of germ-free mice with fecal material from lung cancer immunotherapy responders led to increased T-cell responses, and greater efficacy of anti-PD-1 therapy (4).…”

Demystifying the manipulation of host immunity, metabolism, and extraintestinal tumors by the gut microbiome

“…455 Therefore, there is an urgent need to combat therapeutic resistance and identify biomarkers that can be used to predict the response to ICIs. The high heterogeneity to ICI therapy in cancer patients can be partially explained by differences in gut microbiome composition, with compelling evidence suggesting that gut microbiome and even specific key bacterial taxa potentially contribute to interindividual variation in ICI therapeutic efficacy in numerous clinical cohorts [456][457][458][459][460] and that optimal modulation of the gut microbiome is sufficient to strengthen the therapeutic response to ICIs in preclinical models. 43,461,462 The particular gut microbiome seemingly has a positive influence on the effectiveness of ICIs via manipulating the tumor microenvironment in preclinical models.…”

“…459 Similarly, the gut microbiome potentially exerts a profound effect on the responses of HCC patients receiving anti-PD-1 mAb. 456 Responders exhibit greater taxa richness and 20 responder-enriched species (such as A. muciniphila and Ruminococcaceae spp.) that are associated with carbohydrate catabolism and methanogenesis.…”