Gut microbiome to predict durable response to immunotherapy in patients with hepatocellular carcinoma.

Abstract

47 Background: Patients with hepatocellular carcinoma (HCC) can hardly benefit from immunotherapy (IO); however, few patients develop durable responses to IO (long-responder, LR). Gut microbiota implicate IO response in multiple cancers, while its characteristics in LRs of IO has not been well sketched. With these motivations, we applied metagenomics to comprehensively unveil intestinal flora profiles in LRs, and compare with less responders to investigate its potential in response prediction. Methods: Advanced HCC patients treated with anti-PD-1 with/without anti-CTLA-4 fall into 3 distinct subgroups: non-responders (NRs) presenting early disease progression within 6 months, long responders (LRs) who achieve durable disease control with a minimum of 12 months, and the remaining short responders (SRs). Fresh stool samples were collected for metagenomic sequencing at least 12 months after initiation of a variety of immunotherapy regimens in LRs, while samples were collected within 6 months of IO treatment for NRs and SRs. Metagenome profiles were annotated using Kraken, and significant differences were revealed by Lefse analysis. Results: A total of 66 patients with advanced HCC who received IO first time were enrolled, 38 patients were evaluated as LRs, 8 as SRs, and 20 as NRs. Metagenome profiling unveiled significant association in its diversity and composition with clinical response. The β-diversity increased gradually as the treatment response getting better (p < 0.001). The β-diversity was significantly lower in NRs in comparison with SRs (p < 0.05) and LR (p < 0.001), while there was no significance between SRs and LRs. Significant higher abundance of Clostridium_butyricum was observed in LRs compared with NRs. Moreover, anabolic pathways like fatty acid biogenesis were significantly enriched in LRs. Conclusions: Gut metagenomic diversities and profiles were related with IO response in advanced HCC patients, which could be potential prediction biomarkers of IO durable benefits. The enrichment of probiotics like Clostridium_butyricum and its derived fatty acid have a mechanistic impact on higher antitumor immunity, which need further verification study.