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Review ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.02254

Immunopathogenesis of immune checkpoint inhibitor-related adverse events: roles of the intestinal microbiome and Th17 cells

 Ronald Anderson1*,  Annette J. Theron2 and Bernardo L. Rapoport2
  • 1Department of Immunology, University of Pretoria, South Africa
  • 2Department of Immunology, School of Medicine, University of Pretoria, South Africa

The advent of novel, innovative and effective anti-cancer immunotherapies has engendered an era of renewed optimism among cancer specialists and their patients. Foremost among these successful immunotherapies are monoclonal antibodies (MAbs) which target immune checkpoint inhibitor (ICI) molecules, most prominently cytotoxic T-lymphocyte-associated protein (CTLA-4) and programmed cell death protein-1 (PD-1) and its major ligand, PD-L1. These immunotherapeutic agents are, however, often associated with the occurrence of immune-mediated toxicities known as immune-related adverse events (IRAEs). The incidence of severe toxicities increases substantially when these agents are used together, particularly with CTLA-4 in combination with PD-1 or PD-L1 antagonists. Accordingly, dissociating the beneficial anti-tumor therapeutic activity of these agents from the emergence of IRAEs represents a significant challenge to attaining the optimum efficacy of ICI-targeted immunotherapy of cancer. This situation is compounded by an increasing awareness, possibly unsurprising, that both the beneficial and harmful effects of ICI-targeted therapies appear to result from an over-reactive immune system. Nevertheless, this challenge may not be insurmountable. This contention is based on acquisition of recent insights into the role of the gut microbiome and its products as determinants of the efficacy of ICI-targeted immunotherapy, as well as an increasing realization of the enigmatic involvement of Th17 cells in both anti-tumor activity and the pathogenesis of some types of IRAEs. Evidence linking the beneficial and harmful activities of ICI-targeted immunotherapy, recent mechanistic insights focusing on the gut microbiome and Th17cells, as well as strategies to attenuate IRAEs in the setting of retention of therapeutic activity, therefore represent the major thrusts of this review.

Keywords: Adenosine 5-triphosphate, cytotoxic T-lymphocyte-associated protein (CTLA-4); , ipilimumab, immune-related adverse events (IRAEs); , Interleukin-17, microbiome, Nivolumab, programmed cell death protein-1 (PD-1); , T cell

Received: 01 Jul 2019; Accepted: 06 Sep 2019.

Copyright: © 2019 Anderson, Theron and Rapoport. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Ronald Anderson, University of Pretoria, Department of Immunology, Pretoria, South Africa, ronald.anderson@up.ac.za