Gut microbiome is associated with the clinical response to anti-PD-1 based immunotherapy in hepatobiliary cancers

Abstract

BackgroundThe gut microbiome is associated with the response to immunotherapy for different cancers. However, the impact of the gut microbiome on hepatobiliary cancers receiving immunotherapy remains unknown. This study aims to investigate the relationship between the gut microbiome and the clinical response to anti-programmed cell death protein 1 (PD-1) immunotherapy in patients with advanced hepatobiliary cancers.MethodsPatients with unresectable hepatocellular carcinoma or advanced biliary tract cancers who have progressed from first-line chemotherapy (gemcitabine plus cisplatin) were enrolled. Fresh stool samples were collected before and during anti-PD-1 treatment and analyzed with metagenomic sequencing. Significantly differentially enriched taxa and prognosis associated taxa were identified. The Kyoto Encyclopedia of Genes and Genomes database and MetaCyc database were further applied to annotate the differentially enriched taxa to explore the potential mechanism of the gut microbiome influencing cancer immunotherapy.ResultsIn total, 65 patients with advanced hepatobiliary cancers receiving anti-PD-1 treatment were included in this study. Seventy-four taxa were significantly enriched in the clinical benefit response (CBR) group and 40 taxa were significantly enriched in the non-clinical benefit (NCB) group. Among these taxa, patients with higher abundance of Lachnospiraceae bacterium-GAM79 and Alistipes sp Marseille-P5997, which were significantly enriched in the CBR group, achieved longer progression-free survival (PFS) and overall survival (OS) than patients with lower abundance. Higher abundance of Ruminococcus calidus and Erysipelotichaceae bacterium-GAM147 enriched in the CBR group was also observed in patients with better PFS. In contrast, worse PFS and OS were found in patients with higher abundance of Veillonellaceae, which was significantly enriched in the NCB group. Functional annotation indicated that the taxa enriched in the CBR group were associated with energy metabolism while the taxa enriched in the NCB group were associated with amino acid metabolism, which may modulate the clinical response to immunotherapy in hepatobiliary cancers. In addition, immunotherapy-related adverse events were affected by the gut microbiome diversity and relative abundance.ConclusionsWe demonstrate that the gut microbiome is associated with the clinical response to anti-PD-1 immunotherapy in patients with hepatobiliary cancers. Taxonomic signatures enriched in responders are effective biomarkers to predict the clinical response and survival benefit of immunotherapy, which might provide a new therapeutic target to modulate the response to cancer immunotherapy.

Reproducible stool metagenomic biomarkers linked to the melanoma immunotherapy positive outcome

“…However, only F. prausnitzii is reproducible for all datasets included in the analysis. Identified biomarkers are confirmed by many published studies [Sivan et al, 2015; Chaput et al, 2017; Frankel et al, 2017; Gopalakrishnan et al, 2018; Matson et al, 2018; Jin et al, 2019; Peters et al, 2019; Zheng et al, 2019; Tanoe et al, 2019; Derosa et al, 2020; Coutzac et al, 2020; Limeta et al, 2020; Fedorov et al, 2020; Heshiki et al, 2020; Sun et al, 2020; Lee et al, 2021; Spencer et al, 2021; Mao et al, 2021; Usyk et al, 2021; Lee et al, 2022]. Additionally, we identified 140 KOGs as reproducible functional biomarkers of positive immunotherapy outcome corresponds to fatty acids biosynthesis, polysaccharide biosynthesis and degradation, peptidoglycan and lipopolysaccharide biosynthesis, cobalamin biosynthesis, fructoselysine/glucoselysine utilization system, sporulation, and motility/secretion system.…”

Gut Microbiome and Plasma Metabolomic Analysis in Patients with Myelodysplastic Syndrome

“…In hepatobiliary cancers, a higher abundance of Ruminococcus callidus and Erysipelotrichaceae bacterium-GAM147 was found in patients with longer progression-free survival (PFS), while a higher abundance of Veillonellaceae was found in patients with shorter PFS and overall survival (OS). The gut microbiome is associated with the clinical response to anti-programmed cell death protein 1 (PD-1) therapy in patients with hepatobiliary cancers [ 42 ]. In metastatic melanoma, Faecalibacterium enrichment is associated with a good clinical response to ipilimumab (an immune checkpoint inhibitor targeting CTLA-4) [ 43 ].…”

“…In hepatobiliary cancers, the gut microbiome is related to the response to PD-1 inhibitor treatment. Functional annotation indicated that the taxa enriched in the clinical benefit response group were associated with energy metabolism, whereas those in the non-clinical benefit group were associated with amino acid metabolism, which may modulate the clinical response to immunotherapy [ 42 ]. This indicates that the gut microbiota might regulate host immunity by influencing the metabolism in cancer.…”

Common themes in antimicrobial and anticancer drug resistance

“…The favorable clinical outcome during anti-PD1 therapy was linked to the presence of Akkermansia muciniphila , as well as to high diversity and abundance of Clostridiales/Ruminococcaceae / Faecalibacterium, Bifidobacterium longum , Collinsella aerofaciens , and Enterococcus faecium . Conversely, the poor responders harbored a low diversity and high abundance of Bacteroidales ( Robert et al, 2011 ; Sivan et al, 2015 ; Gopalakrishnan et al, 2018 ; Mao et al, 2021 ; Wong et al, 2021 ; Sevcikova et al, 2022 ).…”