Metagenomic Shotgun Sequencing and Unbiased Metabolomic Profiling Identify Specific Human Gut Microbiota and Metabolites Associated with Immune Checkpoint Therapy Efficacy in Melanoma Patients

Abstract

This is the first prospective study of the effects of human gut microbiota and metabolites on immune checkpoint inhibitor (ICT) response in metastatic melanoma patients. Whereas many melanoma patients exhibit profound response to ICT, there are fewer options for patients failing ICT—particularly with BRAF-wild-type disease. In preclinical studies, specific gut microbiota promotes regression of melanoma in mice. We therefore conducted a study of the effects of pretreatment gut microbiota and metabolites on ICT Response Evaluation Criteria in Solid Tumors response in 39 metastatic melanoma patients treated with ipilimumab, nivolumab, ipilimumab plus nivolumab (IN), or pembrolizumab (P). IN yielded 67% responses and 8% stable disease; P achieved 23% responses and 23% stable disease. ICT responders for all types of therapies were enriched for Bacteroides caccae. Among IN responders, the gut microbiome was enriched for Faecalibacterium prausnitzii, Bacteroides thetaiotamicron, and Holdemania filiformis. Among P responders, the microbiome was enriched for Dorea formicogenerans. Unbiased shotgun metabolomics revealed high levels of anacardic acid in ICT responders. Based on these pilot studies, both additional confirmatory clinical studies and preclinical testing of these bacterial species and metabolites are warranted to confirm their ICT enhancing activity.

The Influence of the Gut Microbiome on Cancer, Immunity, and Cancer Immunotherapy

“…These studies were further supplemented by multiple studies published in the past several months demonstrating a role for the gut microbiota in patients on immune checkpoint blockade (Chaput et al, 2017, Frankel et al, 2017, Gopalakrishnan et al, 2018, Matson et al, 2018, Routy et al, 2018). Several provocative findings were reported substantiating the role of the gut microbiota in shaping responses to therapy.…”

“…Pre- clinical models have demonstrated an improvement in toxicity scores in anti-CTLA-4-treated mice with oral gavage of Bacteroides fragilis and Burkholderia cepacia (Vetizou et al, 2015). The influence of the gut microbiota on toxicity has also been studied in human cohorts (Chaput et al, 2017, Dubin et al, 2016, Frankel et al, 2017) (Figure 2). Taxonomical and functional differences have been reported in anti-CTLA-4 treated melanoma patients who were colitis-free (with enrichment of Bacteroidetes and abundance of genetic pathways involved in polyamine transport and B vitamin synthesis) as opposed to those who developed colitis (Dubin et al, 2016).…”

“…This may be related to the known influence of these factors in Treg differentiation (Round and Mazmanian, 2010, Faith et al, 2014). Additional cohorts have also been studied, showing that patients with a higher abundance of Faecalibacterium prausnitzii and other related Firmicutes and low abundance of Bacteroidetes had a higher risk of colitis on anti-CTLA-4 therapy (Chaput et al, 2017, Frankel et al, 2017). The group also reported that patients with colitis had increased expression of ICOS on the surface of effector CD4 + T-cells and low levels of Tregs and systemic inflammatory proteins such as IL-6, IL-8 and sCD25 in the blood at baseline, which may be related to the compositional differences in the microbiome (Chaput et al, 2017).…”

“…There is mounting evidence supporting the role of the microbiome in response to cancer therapy, with several recent studies demonstrating the influence of the gut microbiome specifically on the response to immune checkpoint blockade across cancer types (Chaput et al, 2017, Frankel et al, 2017, Gopalakrishnan et al, 2018, Matson et al, 2018, Routy et al, 2018). How and why this occurs necessitates an understanding of the intricate web of cancer, immunosurveillance, and the factors that influence both host and anti-tumor immunity – including the gut microbiome.…”

The gut microbiota and immune checkpoint inhibitors

“…in 2017 detected the opposite to Wargo and colleagues, where there were no significant differences in gut microbial diversity between responders and non-responders of immunostimulants. 49 This raises the question of how the baseline diversity of both research groups of non-responders and responders from each publication compared, especially while incorporating patient demographics. Moreover, it would be reasonable to measure the average baseline differences of an individual's profile of gut microbiota relatively amongst different sexes, ages, health conditions, lifestyle, and environment to develop a more standard measurement for future FMT investigations.…”