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Inhibition of immune checkpoints PD-1, CTLA-4, and IDO1 coordinately induces immune-mediated liver injury in mice

Cancer cells harness immune checkpoints such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1) and indoleamine 2,3-dioxygenase 1 (IDO1) to evade immune control. Checkpoint inhibitors have demonstrated durable anti-tumor efficacy in human and preclinical...

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Autores principales: Affolter, Timothy, Llewellyn, Heather P., Bartlett, Derek W., Zong, Qing, Xia, Shuhua, Torti, Vince, Ji, Changhua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6528985/
https://www.ncbi.nlm.nih.gov/pubmed/31112568
http://dx.doi.org/10.1371/journal.pone.0217276
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author Affolter, Timothy
Llewellyn, Heather P.
Bartlett, Derek W.
Zong, Qing
Xia, Shuhua
Torti, Vince
Ji, Changhua
author_facet Affolter, Timothy
Llewellyn, Heather P.
Bartlett, Derek W.
Zong, Qing
Xia, Shuhua
Torti, Vince
Ji, Changhua
author_sort Affolter, Timothy
collection PubMed
description Cancer cells harness immune checkpoints such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1) and indoleamine 2,3-dioxygenase 1 (IDO1) to evade immune control. Checkpoint inhibitors have demonstrated durable anti-tumor efficacy in human and preclinical models. Liver toxicity is one of the common immune-related adverse events associated with checkpoint inhibitors (CPIs) and its frequency and severity often increase significantly during CPI combination therapies. We aim to develop a mouse model to elucidate the immune mechanisms of CPI-associated liver toxicity. Co-administration of CTLA-4 blocking antibody, 9D9, and/or an IDO1 inhibitor, epacadostat in wild-type and PD-1(-/-) mice (to simulate the effect of PD1 blockade) synergistically induced liver injury and immune cell infiltration. Infiltrated cells were primarily composed of CD8+ T cells and positively associated with hepatocyte necrosis. Strikingly, sites of hepatocyte necrosis were frequently surrounded by clusters of mononuclear immune cells. CPI treatments resulted in increased expression of genes associated with hepatocyte cell death, leukocyte migration and T cell activation in the liver. In conclusion, blockade of immune checkpoints PD-1, CTLA-4, and IDO1 act synergistically to enhance T cell infiltration and activity in the liver, leading to hepatocyte death.
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spelling pubmed-65289852019-05-31 Inhibition of immune checkpoints PD-1, CTLA-4, and IDO1 coordinately induces immune-mediated liver injury in mice Affolter, Timothy Llewellyn, Heather P. Bartlett, Derek W. Zong, Qing Xia, Shuhua Torti, Vince Ji, Changhua PLoS One Research Article Cancer cells harness immune checkpoints such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1) and indoleamine 2,3-dioxygenase 1 (IDO1) to evade immune control. Checkpoint inhibitors have demonstrated durable anti-tumor efficacy in human and preclinical models. Liver toxicity is one of the common immune-related adverse events associated with checkpoint inhibitors (CPIs) and its frequency and severity often increase significantly during CPI combination therapies. We aim to develop a mouse model to elucidate the immune mechanisms of CPI-associated liver toxicity. Co-administration of CTLA-4 blocking antibody, 9D9, and/or an IDO1 inhibitor, epacadostat in wild-type and PD-1(-/-) mice (to simulate the effect of PD1 blockade) synergistically induced liver injury and immune cell infiltration. Infiltrated cells were primarily composed of CD8+ T cells and positively associated with hepatocyte necrosis. Strikingly, sites of hepatocyte necrosis were frequently surrounded by clusters of mononuclear immune cells. CPI treatments resulted in increased expression of genes associated with hepatocyte cell death, leukocyte migration and T cell activation in the liver. In conclusion, blockade of immune checkpoints PD-1, CTLA-4, and IDO1 act synergistically to enhance T cell infiltration and activity in the liver, leading to hepatocyte death. Public Library of Science 2019-05-21 /pmc/articles/PMC6528985/ /pubmed/31112568 http://dx.doi.org/10.1371/journal.pone.0217276 Text en © 2019 Affolter et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Affolter, Timothy
Llewellyn, Heather P.
Bartlett, Derek W.
Zong, Qing
Xia, Shuhua
Torti, Vince
Ji, Changhua
Inhibition of immune checkpoints PD-1, CTLA-4, and IDO1 coordinately induces immune-mediated liver injury in mice
title Inhibition of immune checkpoints PD-1, CTLA-4, and IDO1 coordinately induces immune-mediated liver injury in mice
title_full Inhibition of immune checkpoints PD-1, CTLA-4, and IDO1 coordinately induces immune-mediated liver injury in mice
title_fullStr Inhibition of immune checkpoints PD-1, CTLA-4, and IDO1 coordinately induces immune-mediated liver injury in mice
title_full_unstemmed Inhibition of immune checkpoints PD-1, CTLA-4, and IDO1 coordinately induces immune-mediated liver injury in mice
title_short Inhibition of immune checkpoints PD-1, CTLA-4, and IDO1 coordinately induces immune-mediated liver injury in mice
title_sort inhibition of immune checkpoints pd-1, ctla-4, and ido1 coordinately induces immune-mediated liver injury in mice
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6528985/
https://www.ncbi.nlm.nih.gov/pubmed/31112568
http://dx.doi.org/10.1371/journal.pone.0217276
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