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Deciphering the Dynamic Complexities of the Liver Microenvironment — Toward a Better Understanding of Immune-Mediated liver Injury Caused by Immune Checkpoint Inhibitors (ILICI)

  • Review Article
  • Theme: Identification and Implementation of Predictive Biomarkers for Checkpoint Targeted Immunotherapy
  • Published:
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Abstract

Immune checkpoint inhibitors (ICIs) represent a promising therapy for many types of cancer. However, only a portion of patients respond to this therapy and some patients develop clinically significant immune-mediated liver injury caused by immune checkpoint inhibitors (ILICI), an immune-related adverse event (irAE) that may require the interruption or termination of treatment and administration of systemic corticosteroids or other immunosuppressive agents. Although the incidence of ILICI is lower with monotherapy, the surge in combining ICIs with chemotherapy, targeted therapy, and combination of different ICIs has led to an increase in the incidence and severity of ILICI — a major challenge for development of effective and safe ICI therapy. In this review, we highlight the importance and contribution of the liver microenvironment to ILICI by focusing on the emerging roles of resident liver cells in modulating immune homeostasis and hepatocyte regeneration, two important decisive factors that dictate the initiation, progression, and recovery from ILICI. Based on the proposed contribution of the liver microenvironment on ICILI, we discuss the clinical characteristics of ILICI in patients with preexisting liver diseases, as well as the challenges of identifying prognostic biomarkers to guide the clinical management of severe ILICI. A better understanding of the liver microenvironment may lead to novel strategies and identification of novel biomarkers for effective management of ILICI.

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Acknowledgements

The authors are partly supported by a grant from the Office of the Chief Scientist, the US Food and Drug Administration. The authors thank Dr. Steven Lemery for critically reviewing the manuscript.

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The project is partially supported by a grant from the Office of the Chief Scientist, the US Food and Drug Administration.

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T.W. developed the concept for the manuscript and drafted the bulk of the manuscript. M.M.Y, M.I.A, and L.P provided substantial contributions to the conception of the work and critical intellectual content. G.M.F provided critical intellectual content and editorial input, and provided final approval for the work to be published. All authors have agreed to be accountable for all aspects of the work.

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Wang, T., Yeh, M.M., Avigan, M.I. et al. Deciphering the Dynamic Complexities of the Liver Microenvironment — Toward a Better Understanding of Immune-Mediated liver Injury Caused by Immune Checkpoint Inhibitors (ILICI). AAPS J 23, 99 (2021). https://doi.org/10.1208/s12248-021-00629-2

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