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Epigenetic state determines the in vivo efficacy of STING agonist therapy
While STING-activating agents have shown limited efficacy in early-phase clinical trials, multiple lines of evidence suggest the importance of tumor cell-intrinsic STING function in mediating antitumor immune responses. Although STING signaling is impaired in human melanoma, its restoration through...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10033671/ https://www.ncbi.nlm.nih.gov/pubmed/36949064 http://dx.doi.org/10.1038/s41467-023-37217-1 |
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author | Falahat, Rana Berglund, Anders Perez-Villarroel, Patricio Putney, Ryan M. Hamaidi, Imene Kim, Sungjune Pilon-Thomas, Shari Barber, Glen N. Mulé, James J. |
author_facet | Falahat, Rana Berglund, Anders Perez-Villarroel, Patricio Putney, Ryan M. Hamaidi, Imene Kim, Sungjune Pilon-Thomas, Shari Barber, Glen N. Mulé, James J. |
author_sort | Falahat, Rana |
collection | PubMed |
description | While STING-activating agents have shown limited efficacy in early-phase clinical trials, multiple lines of evidence suggest the importance of tumor cell-intrinsic STING function in mediating antitumor immune responses. Although STING signaling is impaired in human melanoma, its restoration through epigenetic reprogramming can augment its antigenicity and T cell recognition. In this study, we show that reversal of methylation silencing of STING in murine melanoma cell lines using a clinically available DNA methylation inhibitor can improve agonist-induced STING activation and type-I IFN induction, which, in tumor-bearing mice, can induce tumor regression through a CD8(+) T cell-dependent immune response. These findings not only provide mechanistic insight into how STING signaling dysfunction in tumor cells can contribute to impaired responses to STING agonist therapy, but also suggest that pharmacological restoration of STING signaling through epigenetic reprogramming might improve the therapeutic efficacy of STING agonists. |
format | Online Article Text |
id | pubmed-10033671 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-100336712023-03-24 Epigenetic state determines the in vivo efficacy of STING agonist therapy Falahat, Rana Berglund, Anders Perez-Villarroel, Patricio Putney, Ryan M. Hamaidi, Imene Kim, Sungjune Pilon-Thomas, Shari Barber, Glen N. Mulé, James J. Nat Commun Article While STING-activating agents have shown limited efficacy in early-phase clinical trials, multiple lines of evidence suggest the importance of tumor cell-intrinsic STING function in mediating antitumor immune responses. Although STING signaling is impaired in human melanoma, its restoration through epigenetic reprogramming can augment its antigenicity and T cell recognition. In this study, we show that reversal of methylation silencing of STING in murine melanoma cell lines using a clinically available DNA methylation inhibitor can improve agonist-induced STING activation and type-I IFN induction, which, in tumor-bearing mice, can induce tumor regression through a CD8(+) T cell-dependent immune response. These findings not only provide mechanistic insight into how STING signaling dysfunction in tumor cells can contribute to impaired responses to STING agonist therapy, but also suggest that pharmacological restoration of STING signaling through epigenetic reprogramming might improve the therapeutic efficacy of STING agonists. Nature Publishing Group UK 2023-03-22 /pmc/articles/PMC10033671/ /pubmed/36949064 http://dx.doi.org/10.1038/s41467-023-37217-1 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Falahat, Rana Berglund, Anders Perez-Villarroel, Patricio Putney, Ryan M. Hamaidi, Imene Kim, Sungjune Pilon-Thomas, Shari Barber, Glen N. Mulé, James J. Epigenetic state determines the in vivo efficacy of STING agonist therapy |
title | Epigenetic state determines the in vivo efficacy of STING agonist therapy |
title_full | Epigenetic state determines the in vivo efficacy of STING agonist therapy |
title_fullStr | Epigenetic state determines the in vivo efficacy of STING agonist therapy |
title_full_unstemmed | Epigenetic state determines the in vivo efficacy of STING agonist therapy |
title_short | Epigenetic state determines the in vivo efficacy of STING agonist therapy |
title_sort | epigenetic state determines the in vivo efficacy of sting agonist therapy |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10033671/ https://www.ncbi.nlm.nih.gov/pubmed/36949064 http://dx.doi.org/10.1038/s41467-023-37217-1 |
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