Akkermansia muciniphila improve anti-PD-1 therapy against hepatocellular carcinoma by increasing host TUDCA synthesis

Abstract The immune checkpoint inhibitor PD-1mAb have shown excellent treatment in a variety of cancers including hepatocellular carcinoma (HCC), However, the patients' response rates are still low and many initial responders might become resistant to the therapy. Akkermansia muciniphila (AKK) is reported to be associated with multiple human diseases. More abundance of AKK was detected in patients who respond well to PD-1mAb, yet the underlying mechanism is not clear. In our study, we found that AKK could enhance the efficacy of PD-1mAb against HCC in a tumor bearing mice model. It can promote HCC tumor cells into apoptosis process and diminish ki-67 expression. It raised the CD8+T proportion in the tumor microenvironment and promoted IFN-γ secretion. Furthermore, it down-regulate PD-L1 expression on tumor cells. Metabonomics analysis demonstrated that AKK altered the host bile acid metabolism and significantly raised the serum TUDCA level. Since FXR is the major receptor for bile acid and both TUDCA and FXR were reported to exert immunosuppresive roles in HCC development. In addition, FXR could negatively regulate PD-L1 expression on tumor surface. Based on these findings, we speculate that AKK might reinforce the immunotherapy of PD-1mAb against HCC through a TUDCA-FXR-PD-L1 pathway. Trial registration: We confirm that the study has been approved by the Institute Ethics Committee at Renji Hospital of Shanghai Jiao Tong University.