Abstract
BackgroundImmune checkpoint blockade (ICB) shows lasting benefits in advanced melanoma; however, not all patients respond to this treatment and many develop potentially life-threatening immune-related adverse events (irAEs). Identifying individuals who will develop irAEs is critical in order to improve the quality of care. Here, we prospectively demonstrate that the gut microbiome predicts irAEs in melanoma patients undergoing ICB.MethodsPre-, during, and post-treatment stool samples were collected from 27 patients with advanced stage melanoma treated with IPI (anti-CTLA-4) and NIVO (anti-PD1) ICB inhibitors at NYU Langone Health. We completed 16S rRNA gene amplicon sequencing, DNA deep shotgun metagenomic, and RNA-seq metatranscriptomic sequencing. The divisive amplicon denoising algorithm (DADA2) was used to process 16S data. Taxonomy for shotgun sequencing data was assigned using MetaPhlAn2, and gene pathways were assigned using HUMAnN 2.0. Compositionally aware differential expression analysis was performed using ANCOM. The Cox-proportional hazard model was used to assess the prospective role of the gut microbiome (GMB) in irAES, with adjustment for age, sex, BMI, immune ICB treatment type, and sequencing batch.ResultsTwo natural GMB clusters with distinct community compositions were identified from the analysis of 16S rRNA data (R2 = 0.16, p < 0.001). In Cox-proportional hazard modeling, these two clusters showed a near 7-fold differential risk for developing irAEs within 1 year of initiating treatment (HR = 6.89 [95% CI: 1.33–35.58]). Using shotgun metagenomics, we further identified 37 bacterial strains differentially expressed between the risk groups, with specific dominance of Bacteroides dorei within the high-risk GMB cluster and Bacteroides vulgatus in the low-risk cluster. The high-risk cluster also appeared to have elevated expression of several functional pathways, including those associated with adenosine metabolism (all FDR < 0.05). A sub-analysis of samples (n = 10 participants) at baseline and 6 and 12 weeks after the start of treatment revealed that the microbiome remained stable over the course of treatment (R2 = 0.88, p < 0.001).ConclusionsWe identified two distinct fecal bacterial community clusters which are associated differentially with irAEs in ICB-treated advanced melanoma patients.
Highlights
Immune checkpoint blockade (ICB) shows lasting benefits in advanced melanoma; not all patients respond to this treatment and many develop potentially life-threatening immune-related adverse events
Based on unsupervised hierarchical clustering at the amplicon sequence variant (ASV) level, two distinct clusters were identified (Fig. 1A). These clusters represented significant differences in the overall gut microbiome (GMB) structure, based on unadjusted PERMANOVA analysis (R2 = 0.16 p < 0.001; Fig. 1B) and with kernel-based covariate adjustment for subject age, sex, BMI, and treatment type (p < 0.001). We examined whether these naturally occurring GMB clusters were associated with immune-related adverse events
In Kaplan-Meir analysis, we showed that immune-related adverse events (irAEs) grade 2+ occurred more frequently for study participants in the GMB1 versus the
Summary
Immune checkpoint blockade (ICB) shows lasting benefits in advanced melanoma; not all patients respond to this treatment and many develop potentially life-threatening immune-related adverse events (irAEs). We prospectively demonstrate that the gut microbiome predicts irAEs in melanoma patients undergoing ICB. Not all patients receiving ICB treatment benefit, and a substantial portion experience immune-related adverse events (irAEs), including colitis, diarrhea, endocrinopathies, rashes, pneumonitis, myocarditis, and hepatitis. Healthy donor fecal microbial transplant (FMT) into melanoma patients was reported to reverse ICB therapy-related colitis, without compromising the success of the cancer treatment [9], suggesting that GMB may be directly involved in the control of irAEs. Cross-sectional studies have identified bacteria associated with irAEs, but the specific taxa that were present were not consistent among studies [10]
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