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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

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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.

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Acknowledgements

This work was supported by KAKENIHI Grant (No. 17H04058) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (K.H.) and Health Labor Science Research Grants from Research on Measures for Intractable Diseases, the Intractable Hepato-Biliary Diseases Study Group in Japan.

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Authors and Affiliations

  1. Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan

    Kaori Yoshimura, Yuko Tamano, Hiep Nguyen Canh, Li Zihan, Dong Le Thanh, Yasunori Sato & Kenichi Harada

  2. Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan

    Takeshi Terashima

  3. Internal Medicine, Karatsu Red Cross Hospital, Karatsu, Japan

    Shinji Shimoda

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  1. Kaori Yoshimura
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  2. Yuko Tamano
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  4. Li Zihan
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Correspondence to Kenichi Harada.

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Yoshimura, K., Tamano, Y., Nguyen Canh, H. et al. 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. Med Mol Morphol 56, 106–115 (2023). https://doi.org/10.1007/s00795-022-00344-7

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