Relating the gut metagenome and metatranscriptome to immunotherapy responses in melanoma patients

Abstract

Background Recent evidence suggests that immunotherapy efficacy in melanoma is modulated by gut microbiota. Few studies have examined this phenomenon in humans, and none have incorporated metatranscriptomics, important for determining expression of metagenomic functions in the microbial community. Methods In melanoma patients undergoing immunotherapy, gut microbiome was characterized in pre-treatment stool using 16S rRNA gene and shotgun metagenome sequencing (n = 27). Transcriptional expression of metagenomic pathways was confirmed with metatranscriptome sequencing in a subset of 17. We examined associations of taxa and metagenomic pathways with progression-free survival (PFS) using 500 × 10-fold cross-validated elastic-net penalized Cox regression. Results Higher microbial community richness was associated with longer PFS in 16S and shotgun data (p < 0.05). Clustering based on overall microbiome composition divided patients into three groups with differing PFS; the low-risk group had 99% lower risk of progression than the high-risk group at any time during follow-up (p = 0.002). Among the species selected in regression, abundance of Bacteroides ovatus, Bacteroides dorei, Bacteroides massiliensis, Ruminococcus gnavus, and Blautia producta were related to shorter PFS, and Faecalibacterium prausnitzii, Coprococcus eutactus, Prevotella stercorea, Streptococcus sanguinis, Streptococcus anginosus, and Lachnospiraceae bacterium 3 1 46FAA to longer PFS. Metagenomic functions related to PFS that had correlated metatranscriptomic expression included risk-associated pathways of l-rhamnose degradation, guanosine nucleotide biosynthesis, and B vitamin biosynthesis. Conclusions This work adds to the growing evidence that gut microbiota are related to immunotherapy outcomes, and identifies, for the first time, transcriptionally expressed metagenomic pathways related to PFS. Further research is warranted on microbial therapeutic targets to improve immunotherapy outcomes.

Gut microbiome stability and dynamics in healthy donors and patients with non-gastrointestinal cancers

“…Across cohorts, patients with non-GI cancers have altered gut microbial communities Given our success integrating results of the MI cohort with those from Zeevi et al 2015, we sought to determine whether similar congruence was observed in the gut microbiome of cancer patients. We focused on those with non-GI tumors, for whom recent publications have demonstrated associations between microbiome composition and positive responses to checkpoint inhibitors (Frankel et al, 2017;Gopalakrishnan et al, 2018;Matson et al, 2018;Peters et al, 2019;Routy et al, 2018). In contrast to colorectal cancer (Thomas et al, 2019), there remains a large gap in our knowledge detailing how the microbiome composition of cancer patients with non-GI indications compares to that of healthy donors.…”

“…In contrast to colorectal cancer (Thomas et al, 2019), there remains a large gap in our knowledge detailing how the microbiome composition of cancer patients with non-GI indications compares to that of healthy donors. To investigate this, we applied our Kraken2/GTDB pipeline to an additional 375 samples from 283 cancer patients across five published cohorts (Frankel et al, 2017;Gopalakrishnan et al, 2018;Matson et al, 2018;Peters et al, 2019;Routy et al, 2018; Fig. S4, A-E).…”

The Tumor and Host Immune Signature, and the Gut Microbiota as Predictive Biomarkers for Immune Checkpoint Inhibitor Response in Melanoma Patients

“…Peter et al [ 135 ], in studies on 27 metastatic melanoma patients, also demonstrated the correlation between gut microbiota composition and ICI therapy effects (anti-PD-1 therapy, n = 14; anti-CTLA-4 therapy, n = 1; anti-PD-1/anti-CTLA-4 therapy, n = 12). Coprococcus eutactus , Prevotella stercorea , Streptococcus sanguinis , Streptococcus anginosus , and Lachnospiraceae bacterium 3 1 46FAA and previously found Faecalibacterium prausnitzii were identified in patients with longer PFS, whereas Bacteroides ovatus , Bacteroides dorei , Bacteroides massiliensis , Ruminococcus gnavus , and Blautia producta were present in the gut microbiota of patients with poor clinical outcomes.…”

Relating Gut Microbiome and Its Modulating Factors to Immunotherapy in Solid Tumors: A Systematic Review

“…The vast majority are prospective studies. Among them, 10 studies [6,9,[12][13][14][15][16][17][18][19] had response/e cacy data and 3 studies [17,20,21] had AEs data using ICI therapy, and 1 study had both [17]. Of note, the documented AEs in that 3 studies [17,20,21] were virtually all irAEs.…”