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Atezolizumab Induces Necroptosis and Contributes to Hepatotoxicity of Human Hepatocytes
Atezolizumab is an immune checkpoint inhibitor (ICI) targeting PD-L1 for treatment of solid malignancies. Immune checkpoints control the immune tolerance, and the adverse events such as hepatotoxicity induced by ICIs are often considered as an immune-related adverse event (irAE). However, PD-L1 is a...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10380327/ https://www.ncbi.nlm.nih.gov/pubmed/37511454 http://dx.doi.org/10.3390/ijms241411694 |
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author | Endo, Yukinori Winarski, Katie L. Sajib, Md Sanaullah Ju, Anna Wu, Wen Jin |
author_facet | Endo, Yukinori Winarski, Katie L. Sajib, Md Sanaullah Ju, Anna Wu, Wen Jin |
author_sort | Endo, Yukinori |
collection | PubMed |
description | Atezolizumab is an immune checkpoint inhibitor (ICI) targeting PD-L1 for treatment of solid malignancies. Immune checkpoints control the immune tolerance, and the adverse events such as hepatotoxicity induced by ICIs are often considered as an immune-related adverse event (irAE). However, PD-L1 is also highly expressed in normal tissues, e.g., hepatocytes. It is still not clear whether, targeting PD-L1 on hepatocytes, the atezolizumab may cause damage to liver cells contributing to hepatotoxicity. Here, we reveal a novel mechanism by which the atezolizumab induces hepatotoxicity in human hepatocytes. We find that the atezolizumab treatment increases a release of LDH in the cell culture medium of human hepatocytes (human primary hepatocytes and THLE-2 cells), decreases cell viability, and inhibits the THLE-2 and THLE-3 cell growth. We demonstrate that both the atezolizumab and the conditioned medium (T-CM) derived from activated T cells can induce necroptosis of the THLE-2 cells, which is underscored by the fact that the atezolizumab and T-CM enhance the phosphorylation of RIP3 and MLKL proteins. Furthermore, we also show that necrostatin-1, a necrosome inhibitor, decreases the amount of phosphorylated RIP3 induced by the atezolizumab, resulting in a reduced LDH release in the culture media of the THLE-2 cells. This finding is further supported by the data that GSK872 (a RIP3 inhibitor) significantly reduced the atezolizumab-induced LDH release. Taken together, our data indicate that the atezolizumab induces PD-L1-mediated necrosome formation, contributing to hepatotoxicity in PD-L1(+)-human hepatocytes. This study provides the molecular basis of the atezolizumab-induced hepatotoxicity and opens a new avenue for developing a novel therapeutic approach to reducing hepatotoxicity induced by ICIs. |
format | Online Article Text |
id | pubmed-10380327 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-103803272023-07-29 Atezolizumab Induces Necroptosis and Contributes to Hepatotoxicity of Human Hepatocytes Endo, Yukinori Winarski, Katie L. Sajib, Md Sanaullah Ju, Anna Wu, Wen Jin Int J Mol Sci Article Atezolizumab is an immune checkpoint inhibitor (ICI) targeting PD-L1 for treatment of solid malignancies. Immune checkpoints control the immune tolerance, and the adverse events such as hepatotoxicity induced by ICIs are often considered as an immune-related adverse event (irAE). However, PD-L1 is also highly expressed in normal tissues, e.g., hepatocytes. It is still not clear whether, targeting PD-L1 on hepatocytes, the atezolizumab may cause damage to liver cells contributing to hepatotoxicity. Here, we reveal a novel mechanism by which the atezolizumab induces hepatotoxicity in human hepatocytes. We find that the atezolizumab treatment increases a release of LDH in the cell culture medium of human hepatocytes (human primary hepatocytes and THLE-2 cells), decreases cell viability, and inhibits the THLE-2 and THLE-3 cell growth. We demonstrate that both the atezolizumab and the conditioned medium (T-CM) derived from activated T cells can induce necroptosis of the THLE-2 cells, which is underscored by the fact that the atezolizumab and T-CM enhance the phosphorylation of RIP3 and MLKL proteins. Furthermore, we also show that necrostatin-1, a necrosome inhibitor, decreases the amount of phosphorylated RIP3 induced by the atezolizumab, resulting in a reduced LDH release in the culture media of the THLE-2 cells. This finding is further supported by the data that GSK872 (a RIP3 inhibitor) significantly reduced the atezolizumab-induced LDH release. Taken together, our data indicate that the atezolizumab induces PD-L1-mediated necrosome formation, contributing to hepatotoxicity in PD-L1(+)-human hepatocytes. This study provides the molecular basis of the atezolizumab-induced hepatotoxicity and opens a new avenue for developing a novel therapeutic approach to reducing hepatotoxicity induced by ICIs. MDPI 2023-07-20 /pmc/articles/PMC10380327/ /pubmed/37511454 http://dx.doi.org/10.3390/ijms241411694 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Endo, Yukinori Winarski, Katie L. Sajib, Md Sanaullah Ju, Anna Wu, Wen Jin Atezolizumab Induces Necroptosis and Contributes to Hepatotoxicity of Human Hepatocytes |
title | Atezolizumab Induces Necroptosis and Contributes to Hepatotoxicity of Human Hepatocytes |
title_full | Atezolizumab Induces Necroptosis and Contributes to Hepatotoxicity of Human Hepatocytes |
title_fullStr | Atezolizumab Induces Necroptosis and Contributes to Hepatotoxicity of Human Hepatocytes |
title_full_unstemmed | Atezolizumab Induces Necroptosis and Contributes to Hepatotoxicity of Human Hepatocytes |
title_short | Atezolizumab Induces Necroptosis and Contributes to Hepatotoxicity of Human Hepatocytes |
title_sort | atezolizumab induces necroptosis and contributes to hepatotoxicity of human hepatocytes |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10380327/ https://www.ncbi.nlm.nih.gov/pubmed/37511454 http://dx.doi.org/10.3390/ijms241411694 |
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