BRD4 Inhibition by AZD5153 Promotes Antitumor Immunity via Depolarizing M2 Macrophages

Front Immunol. 2020 Feb 28:11:89. doi: 10.3389/fimmu.2020.00089. eCollection 2020.

Abstract

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.

Keywords: BRD4 inhibitor; M2 macrophage; high-grade serous ovarian cancer (HGSOC); macrophage repolarization; tumor microenvironment; tumor-associated macrophages.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • CD8-Positive T-Lymphocytes / drug effects
  • Cell Cycle Proteins / antagonists & inhibitors
  • Cell Cycle Proteins / metabolism
  • Cell Line
  • Cytokines / drug effects
  • Drug Interactions
  • Female
  • Healthy Volunteers
  • Heterocyclic Compounds, 2-Ring / pharmacology*
  • Humans
  • Leukocytes, Mononuclear
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Neoplasms / drug therapy*
  • Neoplasms / immunology*
  • Ovarian Neoplasms / drug therapy
  • Piperazines / pharmacology*
  • Pyrazoles
  • Pyridazines
  • T-Lymphocytes, Cytotoxic / drug effects
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / metabolism
  • Tumor Microenvironment
  • Tumor-Associated Macrophages / drug effects*
  • Tumor-Associated Macrophages / metabolism*

Substances

  • Antibodies, Monoclonal, Humanized
  • BRD4 protein, human
  • Cell Cycle Proteins
  • Cytokines
  • Heterocyclic Compounds, 2-Ring
  • Piperazines
  • Pyrazoles
  • Pyridazines
  • Transcription Factors
  • atezolizumab
  • AZD5153