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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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
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.
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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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