Elsevier

Neoplasia

Volume 19, Issue 10, October 2017, Pages 848-855
Neoplasia

Metagenomic Shotgun Sequencing and Unbiased Metabolomic Profiling Identify Specific Human Gut Microbiota and Metabolites Associated with Immune Checkpoint Therapy Efficacy in Melanoma Patients1

https://doi.org/10.1016/j.neo.2017.08.004Get rights and content
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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.

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1

Funding: This work was supported by the Roberta I. and Normal L. Pollock Fund (A.Y.K), the Melanoma Research Fund (A.E.F), Cancer Prevention and Research Institute of Texas (RP150596), T. Boone Pickens Cancer Research Fund (A.E.F.), Cancer Prevention and Research Institute of Texas (RP150596)US National Institute of Health (NIH) grant P30CA142543 (Y.X.), NIH grant 5R01CA152301 (Y.X.), and NIH grant R01CA172211 (Y.X.)