Bacteroides vulgatus and Bacteroides dorei predict immune-related adverse events in immune checkpoint blockade treatment of metastatic melanoma

Abstract

Background Immune 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. Methods Pre-, 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. Results Two 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). Conclusions We identified two distinct fecal bacterial community clusters which are associated differentially with irAEs in ICB-treated advanced melanoma patients.

SARS‐CoV‐2 triggered oxidative stress and abnormal energy metabolism in gut microbiota

“… 44 Its specific colonization was also identified as a low‐risk predictor of immune‐related adverse events in metastatic melanoma. 45 Previous works indicated that Alistipes spp. not only was reduced in COVID‐19 patients but also negatively correlated with COVID‐19 severity, 22 , 46 , 47 which may be contributed to its participation in tryptophan metabolism and protective role in intestinal immune homeostasis.…”

Short-Term Metformin Treatment Enriches Bacteroides dorei in an Obese Liver Steatosis Zucker Rat Model

“…However, we observe that B. dorei is enriched in ObMet while B. vulgatus is enriched in ObC ( Figure 2 and Supplementary Figure 3 ). This pattern, where the ratio of B. dorei to B. vulgatus differs with respect to treatment groups, was also observed in blockade treatments in metastatic melanoma ( Usyk et al, 2021 ) and with host epigenomic alterations of inflammatory bowel disease ( Ryan et al, 2020 ). It was proposed by Ryan et al (2020) , that this pattern may be indicative of colonic-crypt species-specific colonization and competition ( Sonnenburg et al, 2010 ; Lee et al, 2013 ) due to differences in metabolic capabilities ( Gutiérrez and Garrido, 2019 ).…”

“…Bacteroides vulgatus has been associated with the reduced risk of immune-related adverse events ( Usyk et al, 2021 ), including dermatological skin toxicity (where B. dorei anti-correlated) ( Zhang et al, 2021 ). Furthermore, B. vulgatus has been shown to be protective against Escherichia coli induced colitis of interleukin-2-deficient gnotobiotic mice ( Waidmann et al, 2003 ).…”

Cancer cell membrane-coated nanoparticles for bimodal imaging-guided photothermal therapy and docetaxel-enhanced immunotherapy against cancer

“…Some studies have demonstrated that DTX can effectively reverse the immunosuppressive TME by polarizing protumoral M2-phenotype TAMs to tumoricidal M1-phenotype TAMs [ 24 ]. Immunotherapy has received increasing attention due to its ability to activate host defenses to identify, attack, and eradicate cancer cells [ 70 , 71 ]. However, low immune response rate and individual differences undermine its antitumor efficacy.…”