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BPTF inhibits NK cell activity and the abundance of natural cytotoxicity receptor co-ligands
Using syngeneic BALB/c mouse breast cancer models, we show that the chromatin remodeling subunit bromodomain PHD finger transcription factor (BPTF) suppresses natural killer (NK) cell antitumor activity in the tumor microenvironment (TME). In culture, BPTF suppresses direct natural cytotoxicity rece...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5610007/ https://www.ncbi.nlm.nih.gov/pubmed/28969075 http://dx.doi.org/10.18632/oncotarget.17834 |
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author | Mayes, Kimberly Elsayed, Zeinab Alhazmi, Aiman Waters, Michael Alkhatib, Suehyb G. Roberts, Mark Song, Carolyn Peterson, Kristen Chan, Vivian Ailaney, Nikhil Malapati, Pumoli Blevins, Tana Lisnić, Berislav Dumur, Catherine I. Landry, Joseph W. |
author_facet | Mayes, Kimberly Elsayed, Zeinab Alhazmi, Aiman Waters, Michael Alkhatib, Suehyb G. Roberts, Mark Song, Carolyn Peterson, Kristen Chan, Vivian Ailaney, Nikhil Malapati, Pumoli Blevins, Tana Lisnić, Berislav Dumur, Catherine I. Landry, Joseph W. |
author_sort | Mayes, Kimberly |
collection | PubMed |
description | Using syngeneic BALB/c mouse breast cancer models, we show that the chromatin remodeling subunit bromodomain PHD finger transcription factor (BPTF) suppresses natural killer (NK) cell antitumor activity in the tumor microenvironment (TME). In culture, BPTF suppresses direct natural cytotoxicity receptor (NCR) mediated NK cell cytolytic activity to mouse and human cancer cell lines, demonstrating conserved functions. Blocking mouse NCR1 in vivo rescues BPTF KD tumor weights, demonstrating its importance for the control of tumor growth. We discovered that BPTF occupies heparanase (Hpse) regulatory elements, activating its expression. Increased heparanase activity results in reduced cell surface abundance of the NCR co-ligands: heparan sulfate proteoglycans (HSPGs). Using gain and loss of function approaches we show that elevated heparanase levels suppress NK cell cytolytic activity to tumor cells in culture. These results suggest that BPTF activates heparanase expression, which in turn reduces cell surface HSPGs and NCR co-ligands, inhibiting NK cell activity. Furthermore, gene expression data from human breast cancer tumors shows that elevated BPTF expression correlates with reduced antitumor immune cell signatures, supporting conserved roles for BPTF in suppressing antitumor immunity. Conditional BPTF depletion in established mouse breast tumors enhances antitumor immunity, suggesting that inhibiting BPTF could provide a novel immunotherapy. |
format | Online Article Text |
id | pubmed-5610007 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-56100072017-09-29 BPTF inhibits NK cell activity and the abundance of natural cytotoxicity receptor co-ligands Mayes, Kimberly Elsayed, Zeinab Alhazmi, Aiman Waters, Michael Alkhatib, Suehyb G. Roberts, Mark Song, Carolyn Peterson, Kristen Chan, Vivian Ailaney, Nikhil Malapati, Pumoli Blevins, Tana Lisnić, Berislav Dumur, Catherine I. Landry, Joseph W. Oncotarget Research Paper Using syngeneic BALB/c mouse breast cancer models, we show that the chromatin remodeling subunit bromodomain PHD finger transcription factor (BPTF) suppresses natural killer (NK) cell antitumor activity in the tumor microenvironment (TME). In culture, BPTF suppresses direct natural cytotoxicity receptor (NCR) mediated NK cell cytolytic activity to mouse and human cancer cell lines, demonstrating conserved functions. Blocking mouse NCR1 in vivo rescues BPTF KD tumor weights, demonstrating its importance for the control of tumor growth. We discovered that BPTF occupies heparanase (Hpse) regulatory elements, activating its expression. Increased heparanase activity results in reduced cell surface abundance of the NCR co-ligands: heparan sulfate proteoglycans (HSPGs). Using gain and loss of function approaches we show that elevated heparanase levels suppress NK cell cytolytic activity to tumor cells in culture. These results suggest that BPTF activates heparanase expression, which in turn reduces cell surface HSPGs and NCR co-ligands, inhibiting NK cell activity. Furthermore, gene expression data from human breast cancer tumors shows that elevated BPTF expression correlates with reduced antitumor immune cell signatures, supporting conserved roles for BPTF in suppressing antitumor immunity. Conditional BPTF depletion in established mouse breast tumors enhances antitumor immunity, suggesting that inhibiting BPTF could provide a novel immunotherapy. Impact Journals LLC 2017-05-12 /pmc/articles/PMC5610007/ /pubmed/28969075 http://dx.doi.org/10.18632/oncotarget.17834 Text en Copyright: © 2017 Mayes et al. http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Research Paper Mayes, Kimberly Elsayed, Zeinab Alhazmi, Aiman Waters, Michael Alkhatib, Suehyb G. Roberts, Mark Song, Carolyn Peterson, Kristen Chan, Vivian Ailaney, Nikhil Malapati, Pumoli Blevins, Tana Lisnić, Berislav Dumur, Catherine I. Landry, Joseph W. BPTF inhibits NK cell activity and the abundance of natural cytotoxicity receptor co-ligands |
title | BPTF inhibits NK cell activity and the abundance of natural cytotoxicity receptor co-ligands |
title_full | BPTF inhibits NK cell activity and the abundance of natural cytotoxicity receptor co-ligands |
title_fullStr | BPTF inhibits NK cell activity and the abundance of natural cytotoxicity receptor co-ligands |
title_full_unstemmed | BPTF inhibits NK cell activity and the abundance of natural cytotoxicity receptor co-ligands |
title_short | BPTF inhibits NK cell activity and the abundance of natural cytotoxicity receptor co-ligands |
title_sort | bptf inhibits nk cell activity and the abundance of natural cytotoxicity receptor co-ligands |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5610007/ https://www.ncbi.nlm.nih.gov/pubmed/28969075 http://dx.doi.org/10.18632/oncotarget.17834 |
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