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Abrogation of IFN-γ Signaling May not Worsen Sensitivity to PD-1/PD-L1 Blockade
Programmed cell death protein 1 (PD-1)/PD-1 ligand 1 (PD-L1) blockade is a promising therapy for various cancer types, but most patients are still resistant. Therefore, a larger number of predictive biomarkers is necessary. In this study, we assessed whether a loss-of-function mutation of the interf...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084912/ https://www.ncbi.nlm.nih.gov/pubmed/32155707 http://dx.doi.org/10.3390/ijms21051806 |
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author | Vackova, Julie Piatakova, Adrianna Polakova, Ingrid Smahel, Michal |
author_facet | Vackova, Julie Piatakova, Adrianna Polakova, Ingrid Smahel, Michal |
author_sort | Vackova, Julie |
collection | PubMed |
description | Programmed cell death protein 1 (PD-1)/PD-1 ligand 1 (PD-L1) blockade is a promising therapy for various cancer types, but most patients are still resistant. Therefore, a larger number of predictive biomarkers is necessary. In this study, we assessed whether a loss-of-function mutation of the interferon (IFN)-γ receptor 1 (IFNGR1) in tumor cells can interfere with anti-PD-L1 therapy. For this purpose, we used the mouse oncogenic TC-1 cell line expressing PD-L1 and major histocompatibility complex class I (MHC-I) molecules and its TC-1/A9 clone with reversibly downregulated PD-L1 and MHC-I expression. Using the CRISPR/Cas9 system, we generated cells with deactivated IFNGR1 (TC-1/dIfngr1 and TC-1/A9/dIfngr1). In tumors, IFNGR1 deactivation did not lead to PD-L1 or MHC-I reduction on tumor cells. From potential inducers, mainly IFN-α and IFN-β enhanced PD-L1 and MHC-I expression on TC-1/dIfngr1 and TC-1/A9/dIfngr1 cells in vitro. Neutralization of the IFN-α/IFN-β receptor confirmed the effect of these cytokines in vivo. Combined immunotherapy with PD-L1 blockade and DNA vaccination showed that IFNGR1 deactivation did not reduce tumor sensitivity to anti-PD-L1. Thus, the impairment of IFN-γ signaling may not be sufficient for PD-L1 and MHC-I reduction on tumor cells and resistance to PD-L1 blockade, and thus should not be used as a single predictive marker for anti-PD-1/PD-L1 cancer therapy. |
format | Online Article Text |
id | pubmed-7084912 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-70849122020-03-23 Abrogation of IFN-γ Signaling May not Worsen Sensitivity to PD-1/PD-L1 Blockade Vackova, Julie Piatakova, Adrianna Polakova, Ingrid Smahel, Michal Int J Mol Sci Article Programmed cell death protein 1 (PD-1)/PD-1 ligand 1 (PD-L1) blockade is a promising therapy for various cancer types, but most patients are still resistant. Therefore, a larger number of predictive biomarkers is necessary. In this study, we assessed whether a loss-of-function mutation of the interferon (IFN)-γ receptor 1 (IFNGR1) in tumor cells can interfere with anti-PD-L1 therapy. For this purpose, we used the mouse oncogenic TC-1 cell line expressing PD-L1 and major histocompatibility complex class I (MHC-I) molecules and its TC-1/A9 clone with reversibly downregulated PD-L1 and MHC-I expression. Using the CRISPR/Cas9 system, we generated cells with deactivated IFNGR1 (TC-1/dIfngr1 and TC-1/A9/dIfngr1). In tumors, IFNGR1 deactivation did not lead to PD-L1 or MHC-I reduction on tumor cells. From potential inducers, mainly IFN-α and IFN-β enhanced PD-L1 and MHC-I expression on TC-1/dIfngr1 and TC-1/A9/dIfngr1 cells in vitro. Neutralization of the IFN-α/IFN-β receptor confirmed the effect of these cytokines in vivo. Combined immunotherapy with PD-L1 blockade and DNA vaccination showed that IFNGR1 deactivation did not reduce tumor sensitivity to anti-PD-L1. Thus, the impairment of IFN-γ signaling may not be sufficient for PD-L1 and MHC-I reduction on tumor cells and resistance to PD-L1 blockade, and thus should not be used as a single predictive marker for anti-PD-1/PD-L1 cancer therapy. MDPI 2020-03-06 /pmc/articles/PMC7084912/ /pubmed/32155707 http://dx.doi.org/10.3390/ijms21051806 Text en © 2020 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Vackova, Julie Piatakova, Adrianna Polakova, Ingrid Smahel, Michal Abrogation of IFN-γ Signaling May not Worsen Sensitivity to PD-1/PD-L1 Blockade |
title | Abrogation of IFN-γ Signaling May not Worsen Sensitivity to PD-1/PD-L1 Blockade |
title_full | Abrogation of IFN-γ Signaling May not Worsen Sensitivity to PD-1/PD-L1 Blockade |
title_fullStr | Abrogation of IFN-γ Signaling May not Worsen Sensitivity to PD-1/PD-L1 Blockade |
title_full_unstemmed | Abrogation of IFN-γ Signaling May not Worsen Sensitivity to PD-1/PD-L1 Blockade |
title_short | Abrogation of IFN-γ Signaling May not Worsen Sensitivity to PD-1/PD-L1 Blockade |
title_sort | abrogation of ifn-γ signaling may not worsen sensitivity to pd-1/pd-l1 blockade |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084912/ https://www.ncbi.nlm.nih.gov/pubmed/32155707 http://dx.doi.org/10.3390/ijms21051806 |
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