A novel pathologic marker, indoleamine 2,3-dioxygenase 1, for the cholangiopathy of immune checkpoint inhibitors-induced immune mediated hepatotoxicity as adverse events and the prediction of additional ursodeoxycholic acid treatment.

Abstract

Immune-related adverse events (irAE) has been clarified according the usage of immune checkpoint inhibitors(ICI). We primarily found indoleamine 2,3-dioxygenase 1(IDO-1) as a histologic biomarker for the cholangiopathy of primary biliary cholangitis(PBC). In this study, we evaluated the utility of IDO-1 in identifying ICI-induced immune-mediated hepatotoxicity(IMH). Immunostaining for IDO-1 using liver sections of PBC, ICI-induced IMH and controls, revealed that IDO-1 expression in bile ducts is mostly restricted in PBC and ICI-induced IMH. In ICI-induced IMH, IDO-1-positive bile ducts is found in 2/2 cases of cholangitis type and also positive/focal ducts in 11/15 cases of hepatitis type. Moreover, in 8/13 positive/focal cases, ursodeoxycholic acid as well as steroids were needed to improve liver dysfunction, but just one case (1/4) in IDO-1-negative cases. One IDO-1 positive case of hepatitis type did not receive additional UDCA, but biliary enzymes worsen. In vitro study using cultured human biliary epithelial cells revealed that IDO-1 induction was found with the stimulation of IFN-γ. In conclusion, the presence of IDO-1-positive cells is found in bile ducts in hepatitic type as well as sclerosing cholangitis of ICI-induced IMH. IDO-1 is surely a valuable pathologic marker for diagnosing ICI-induced IMH and also for predicting an additional need of UDCA in clinical practice.