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BRD4 Inhibition by AZD5153 Promotes Antitumor Immunity via Depolarizing M2 Macrophages

High-grade serous ovarian cancer (HGSOC), with its high recurrence rates, urges for reasonable therapeutic strategies that can prolong overall survival. A tumor microenvironment (TME) discloses prognostic and prospective information on cancer, such as the expression level of PD-1 or PD-L1. However,...

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Autores principales: Li, Xi, Fu, Yu, Yang, Bin, Guo, Ensong, Wu, Yifan, Huang, Jia, Zhang, Xiaoxiao, Xiao, Rourou, Li, Kezhen, Wang, Beibei, Hu, Junbo, Sun, Chaoyang, Chen, Gang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058627/
https://www.ncbi.nlm.nih.gov/pubmed/32184777
http://dx.doi.org/10.3389/fimmu.2020.00089
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author Li, Xi
Fu, Yu
Yang, Bin
Guo, Ensong
Wu, Yifan
Huang, Jia
Zhang, Xiaoxiao
Xiao, Rourou
Li, Kezhen
Wang, Beibei
Hu, Junbo
Sun, Chaoyang
Chen, Gang
author_facet Li, Xi
Fu, Yu
Yang, Bin
Guo, Ensong
Wu, Yifan
Huang, Jia
Zhang, Xiaoxiao
Xiao, Rourou
Li, Kezhen
Wang, Beibei
Hu, Junbo
Sun, Chaoyang
Chen, Gang
author_sort Li, Xi
collection PubMed
description High-grade serous ovarian cancer (HGSOC), with its high recurrence rates, urges for reasonable therapeutic strategies that can prolong overall survival. A tumor microenvironment (TME) discloses prognostic and prospective information on cancer, such as the expression level of PD-1 or PD-L1. However, in HGSOC, the impact of the therapies aiming at these targets remains unsatisfying. Tumor-associated macrophages (TAMs) in HGSOC make up a large part of the TMEs and transform between diverse phenotypes under different treatments. AZD5153 inhibiting BRD4, as a potential therapeutic strategy for HGSOC, was demonstrated to confer controversial plasticity on TAMs, which shows the need to uncover its impact on TAMs in HGSOC. Therefore, we established models for TAMs and TAMs co-culturing with T lymphocytes in vitro. Via RT-PCR and flow cytometry, we find that AZD5153 resets TAMs from M2-type macrophages to M1-like macrophages, consequently promoting pro-inflammatory cytokine secretion and thus activating CD8(+) cytotoxic T lymphocytes (CTLs) in vitro. This modification occurs on MAF transcripts in TAMs and modified by BRD4, which is the target of AZD5153. Importantly, the 3-D microfluid model demonstrates that AZD5153 sensitizes ovarian cancer to anti-PD-L1 therapy. Our results clarify that besides eliminating tumor cells directly, AZD5153 works as a regulator of the TAM phenotype, providing a novel strategy combining AZD5153 and PD-1/PD-L1 antibody that could benefit HGSOC patients.
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spelling pubmed-70586272020-03-17 BRD4 Inhibition by AZD5153 Promotes Antitumor Immunity via Depolarizing M2 Macrophages Li, Xi Fu, Yu Yang, Bin Guo, Ensong Wu, Yifan Huang, Jia Zhang, Xiaoxiao Xiao, Rourou Li, Kezhen Wang, Beibei Hu, Junbo Sun, Chaoyang Chen, Gang Front Immunol Immunology High-grade serous ovarian cancer (HGSOC), with its high recurrence rates, urges for reasonable therapeutic strategies that can prolong overall survival. A tumor microenvironment (TME) discloses prognostic and prospective information on cancer, such as the expression level of PD-1 or PD-L1. However, in HGSOC, the impact of the therapies aiming at these targets remains unsatisfying. Tumor-associated macrophages (TAMs) in HGSOC make up a large part of the TMEs and transform between diverse phenotypes under different treatments. AZD5153 inhibiting BRD4, as a potential therapeutic strategy for HGSOC, was demonstrated to confer controversial plasticity on TAMs, which shows the need to uncover its impact on TAMs in HGSOC. Therefore, we established models for TAMs and TAMs co-culturing with T lymphocytes in vitro. Via RT-PCR and flow cytometry, we find that AZD5153 resets TAMs from M2-type macrophages to M1-like macrophages, consequently promoting pro-inflammatory cytokine secretion and thus activating CD8(+) cytotoxic T lymphocytes (CTLs) in vitro. This modification occurs on MAF transcripts in TAMs and modified by BRD4, which is the target of AZD5153. Importantly, the 3-D microfluid model demonstrates that AZD5153 sensitizes ovarian cancer to anti-PD-L1 therapy. Our results clarify that besides eliminating tumor cells directly, AZD5153 works as a regulator of the TAM phenotype, providing a novel strategy combining AZD5153 and PD-1/PD-L1 antibody that could benefit HGSOC patients. Frontiers Media S.A. 2020-02-28 /pmc/articles/PMC7058627/ /pubmed/32184777 http://dx.doi.org/10.3389/fimmu.2020.00089 Text en Copyright © 2020 Li, Fu, Yang, Guo, Wu, Huang, Zhang, Xiao, Li, Wang, Hu, Sun and Chen. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Li, Xi
Fu, Yu
Yang, Bin
Guo, Ensong
Wu, Yifan
Huang, Jia
Zhang, Xiaoxiao
Xiao, Rourou
Li, Kezhen
Wang, Beibei
Hu, Junbo
Sun, Chaoyang
Chen, Gang
BRD4 Inhibition by AZD5153 Promotes Antitumor Immunity via Depolarizing M2 Macrophages
title BRD4 Inhibition by AZD5153 Promotes Antitumor Immunity via Depolarizing M2 Macrophages
title_full BRD4 Inhibition by AZD5153 Promotes Antitumor Immunity via Depolarizing M2 Macrophages
title_fullStr BRD4 Inhibition by AZD5153 Promotes Antitumor Immunity via Depolarizing M2 Macrophages
title_full_unstemmed BRD4 Inhibition by AZD5153 Promotes Antitumor Immunity via Depolarizing M2 Macrophages
title_short BRD4 Inhibition by AZD5153 Promotes Antitumor Immunity via Depolarizing M2 Macrophages
title_sort brd4 inhibition by azd5153 promotes antitumor immunity via depolarizing m2 macrophages
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058627/
https://www.ncbi.nlm.nih.gov/pubmed/32184777
http://dx.doi.org/10.3389/fimmu.2020.00089
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