Metagenomic shotgun sequencing to identify specific human gut microbes associated with immune checkpoint therapy efficacy in melanoma patients.

Abstract

9516 Background: Immune checkpoint inhibitor therapy, ICT, achieves durable remissions in 30-50% of patients (pts) with metastatic melanoma (Larkin et al. NEJM 2015). It is still unclear what host factors modulate response to ICT. Preclinical mouse studies with B16 melanoma demonstrated that ICT response was dependent on the presence of specific commensal gut bacteria (Vetizou et al. Science 2015; Sivan et al. Science2015). These specific gut bacteria induced the maturation of dendritic cells (DCs) and T-cells needed for effective ICT. We sought to determine whether specific gut microbiota are associated with improved response to ICT in melanoma patients. Methods: 37 melanoma pts treated with ICT (nivolumab plus ipilimumab or pembrolizumab alone) at UTSW Medical Center were enrolled. Fecal samples were collected prior to ICT. Genomic DNA was extracted, and metagenomic shotgun sequencing (MSS) performed on an Illumina HiSeq 2500 PE-100. Taxonomic (MetaPhlAn) and functional (HUMAnN) analysis was performed on MSS data. Disease status was assessed by CT scans and physical exams every two months. Results: Among the 23 evaluable pts, 8 were classified as RECIST responders, 5 with stable disease and 10 with progression. RECIST responder microbiomes were significantly enriched with Methanobrevibacter smithii(p = 0.03; LDA coupled with effect size measurements, LEfSe; Kruskal-Wallis test) , Bacteroides thetaiotamicron(p = 0.03) , Lactobacillus plantarum(p = 0.04), and Eubacterium limosum(p = 0.01) compared to those with progressive disease. Conclusions: MSS identified 4 specific gut microbiota associated with improved response to ICT therapy in melanoma pts. All of these bacteria have been shown to modulate host immune response (Bang PLoS One 2014; Hickey Cell Host Microbe 2016; Rigaux Allergy 2009; Kaunachi World J Gastroentertol 2006). To gain mechanistic insight and confirm causality, shotgun metabolomics on the same fecal specimens used for MSS, in vitroimmune cell assays using the gut microbiota identified, and preclinical modeling in a mouse melanoma model with ICT are underway. These studies may lay the foundation for optimizing the host response to ICT.