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EZH2 inhibition promotes tumor immunogenicity in lung squamous cell carcinomas

Two important factors that contribute to resistance to immune checkpoint inhibitors (ICIs) are an immune-suppressive microenvironment and limited antigen presentation by tumor cells. In this study, we examine if inhibition of the methyltransferase EZH2 can increase ICI response in lung squamous cell...

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Autores principales: DuCote, Tanner J., Song, Xiulong, Naughton, Kassandra J., Chen, Fan, Plaugher, Daniel R., Childress, Avery R., Edgin, Abigail R., Qu, Xufeng, Liu, Jinze, Liu, Jinpeng, Li, Fei, Wong, Kwok-Kin, Brainson, Christine F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10274685/
https://www.ncbi.nlm.nih.gov/pubmed/37333199
http://dx.doi.org/10.1101/2023.06.06.543919
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author DuCote, Tanner J.
Song, Xiulong
Naughton, Kassandra J.
Chen, Fan
Plaugher, Daniel R.
Childress, Avery R.
Edgin, Abigail R.
Qu, Xufeng
Liu, Jinze
Liu, Jinpeng
Li, Fei
Wong, Kwok-Kin
Brainson, Christine F.
author_facet DuCote, Tanner J.
Song, Xiulong
Naughton, Kassandra J.
Chen, Fan
Plaugher, Daniel R.
Childress, Avery R.
Edgin, Abigail R.
Qu, Xufeng
Liu, Jinze
Liu, Jinpeng
Li, Fei
Wong, Kwok-Kin
Brainson, Christine F.
author_sort DuCote, Tanner J.
collection PubMed
description Two important factors that contribute to resistance to immune checkpoint inhibitors (ICIs) are an immune-suppressive microenvironment and limited antigen presentation by tumor cells. In this study, we examine if inhibition of the methyltransferase EZH2 can increase ICI response in lung squamous cell carcinomas (LSCCs). Our in vitro experiments using 2D human cancer cell lines as well as 3D murine and patient derived organoids treated with two inhibitors of the EZH2 plus interferon-γ (IFNγ) showed that EZH2 inhibition leads to expression of both major histocompatibility complex class I and II (MHCI/II) expression at both the mRNA and protein levels. ChIP-sequencing confirmed loss of EZH2-mediated histone marks and gain of activating histone marks at key loci. Further, we demonstrate strong tumor control in models of both autochthonous and syngeneic LSCC treated with anti-PD1 immunotherapy with EZH2 inhibition. Single-cell RNA sequencing and immune cell profiling demonstrated phenotypic changes towards more tumor suppressive phenotypes in EZH2 inhibitor treated tumors. These results indicate that this therapeutic modality could increase ICI responses in patients undergoing treatment for LSCC.
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spelling pubmed-102746852023-06-17 EZH2 inhibition promotes tumor immunogenicity in lung squamous cell carcinomas DuCote, Tanner J. Song, Xiulong Naughton, Kassandra J. Chen, Fan Plaugher, Daniel R. Childress, Avery R. Edgin, Abigail R. Qu, Xufeng Liu, Jinze Liu, Jinpeng Li, Fei Wong, Kwok-Kin Brainson, Christine F. bioRxiv Article Two important factors that contribute to resistance to immune checkpoint inhibitors (ICIs) are an immune-suppressive microenvironment and limited antigen presentation by tumor cells. In this study, we examine if inhibition of the methyltransferase EZH2 can increase ICI response in lung squamous cell carcinomas (LSCCs). Our in vitro experiments using 2D human cancer cell lines as well as 3D murine and patient derived organoids treated with two inhibitors of the EZH2 plus interferon-γ (IFNγ) showed that EZH2 inhibition leads to expression of both major histocompatibility complex class I and II (MHCI/II) expression at both the mRNA and protein levels. ChIP-sequencing confirmed loss of EZH2-mediated histone marks and gain of activating histone marks at key loci. Further, we demonstrate strong tumor control in models of both autochthonous and syngeneic LSCC treated with anti-PD1 immunotherapy with EZH2 inhibition. Single-cell RNA sequencing and immune cell profiling demonstrated phenotypic changes towards more tumor suppressive phenotypes in EZH2 inhibitor treated tumors. These results indicate that this therapeutic modality could increase ICI responses in patients undergoing treatment for LSCC. Cold Spring Harbor Laboratory 2023-06-08 /pmc/articles/PMC10274685/ /pubmed/37333199 http://dx.doi.org/10.1101/2023.06.06.543919 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
DuCote, Tanner J.
Song, Xiulong
Naughton, Kassandra J.
Chen, Fan
Plaugher, Daniel R.
Childress, Avery R.
Edgin, Abigail R.
Qu, Xufeng
Liu, Jinze
Liu, Jinpeng
Li, Fei
Wong, Kwok-Kin
Brainson, Christine F.
EZH2 inhibition promotes tumor immunogenicity in lung squamous cell carcinomas
title EZH2 inhibition promotes tumor immunogenicity in lung squamous cell carcinomas
title_full EZH2 inhibition promotes tumor immunogenicity in lung squamous cell carcinomas
title_fullStr EZH2 inhibition promotes tumor immunogenicity in lung squamous cell carcinomas
title_full_unstemmed EZH2 inhibition promotes tumor immunogenicity in lung squamous cell carcinomas
title_short EZH2 inhibition promotes tumor immunogenicity in lung squamous cell carcinomas
title_sort ezh2 inhibition promotes tumor immunogenicity in lung squamous cell carcinomas
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10274685/
https://www.ncbi.nlm.nih.gov/pubmed/37333199
http://dx.doi.org/10.1101/2023.06.06.543919
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