Gut Microbiome Modulates Response To Anti-PD-1 Immunotherapy In Hepatobiliary Cancers

Background:The response of immunotherapy in advanced hepatobiliary cancers is limited due to lack of effective response and prognosis predictive biomarkers.The gut microbiome modulates the response to immunotherapy across different cancers,however,the impact of gut microbiome on hepatobiliary cancers receiving immunotherapy remains unknown.This study aims to investigate the relationship between the gut microbiome and clinical response of anti-PD-1 immunotherapy in patients with advanced hepatobiliary cancers.Methods:Patients with unresectable hepatocellular carcinoma or advanced biliary tract cancers progressed from the first-line chemotherapy(gemcitabine plus cisplatin)were enrolled in this study.Fresh stool samples were collected before and during treatment and were analyzed with metagenomic sequencing.Significantly differential enriched taxa were identified between clinical benefit response(CBR)group and non-clinical benefit(NCB)group with linear discriminant analysis effect size(LEfSe)and prognosis associated taxa were identified with survival analysis.KEGG database and MetaCyc database were further applied to annotate the differential taxa to explore the potential mechanism of gut microbiome influencing cancer immunotherapy.Results:In total,65 patients with advanced hepatobiliary cancers were included in this study.Seventy-four taxa were significantly enriched in the CBR group and forty taxa were significantly enriched in the NCB group.Among them,higher abundance of Lachnospiraceae bacterium-GAM79,which was significantly enriched in the CBR group(p=0.016),achieved longer progression-free survival(PFS)(P=0.020)and overall survival(OS)(P=0.023)compared to those patients with lower abundance.Ruminococcus calidus and Erysipelotichaceae bacterium-GAM147 enriched in the CBR group were also observed in patients with better PFS(P=0.006,P=0.009).Considering species belonging to the most abundant phylum,Bacteroidetes phylum,patients with higher abundance of Alistipes sp.Marseille-P5997 had significantly better PFS(p=0.013)and OS(p=0.021)than those patients with lower abundance.On the contrary,poor PFS and OS were found in patients with higher abundance of Veillonellaceae enriched in the NCB group(p=0.018,p=0.001).Functional annotation demonstrated that the taxa enriched in the CBR group were associated with energy metabolism such as NAD biosynthesis while the taxa enriched in the NCB group were associated with amino acids metabolism such as arginine biosynthesis,which may modulate the clinical response to immunotherapy via involving secondary bile acid metabolism in hepatobiliary cancers.In addition,the immunotherapy-related adverse events were affected by the gut microbiome diversity and relative abundance.Conclusion:In conclusion,we demonstrated that the gut microbiome influenced the anti-PD-1 immunotherapy in patients with hepatobiliary cancers.Taxonomic signatures,such as higher abundance of Lachnospiraceae bacterium-GAM79,Alistipes sp.Marseille-P5997 and lower abundance of Veillonellaceae,might be an effective biomarker to predict the clinical response and survival benefit.