BRD4 Inhibition by AZD5153 Promotes Antitumor Immunity via Depolarizing M2 Macrophages

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.

Epigenetic Mechanisms of Resistance to Immune Checkpoint Inhibitors

“…Small molecule inhibitors, shown to act as immunomodulatory agents, have been developed and could be combined with immunotherapies to enhance response rates. In ovarian cancer, BRD4 inhibition was shown to reprogram tumor-infiltrating macrophages from the M2-type to M1-type, promoting proinflammatory cytokine secretion and the subsequent activation of CD8+ T cells [ 85 ], and, in prostate cancer, BRD4 inhibition was associated with an increased expression of MHC 1 genes by tumor cells, modification of the global gene expression with an activation of antigen-processing networks and an increased CD8+ T cells/Tregs ratio [ 86 ]. Altogether, many studies support the potential of BET inhibitors to promote antitumor immune responses.…”

The Perfect Combination: Enhancing Patient Response to PD-1-Based Therapies in Epithelial Ovarian Cancer

“…There have been a host of in vivo EOC preclinical studies that have examined a variety of targeted agents in combination with PD-1. Li et al used an in vitro three-dimensional microfluidic model to show that treatment with a bromodomain containing 4 (BRD4) specific inhibitor, AZD5153, decreased PD-L1 levels on M2 macrophages [ 124 ]. BRD4 is a member of the bromodomain and extra terminal (BET) family which is responsible for the promotion of c-myc, resulting in increased cell proliferation.…”

“…BRD4 is a member of the bromodomain and extra terminal (BET) family which is responsible for the promotion of c-myc, resulting in increased cell proliferation. When AZD5153 was tested in combination with anti-PD-L1 therapy in vivo, dual treatment produced a synergistic reduction in tumor burden [ 124 ]. Crawford et al reported efficacy of the combinatorial treatment of a PD-1 monoclonal antibody with REGN4018, a bispecific antibody against mucin 16 (MUC16), a glycoprotein frequently overexpressed in EOC.…”

Histone Deacetylase Inhibitors to Overcome Resistance to Targeted and Immuno Therapy in Metastatic Melanoma

“…Activation of EGFR-STAT3 signaling is responsible for the increased expression of PD-L1 in melanoma cells (Ehexige et al, 2020;Li et al, 2020, Figure 4A). The MAPK and PI3K/AKT signaling pathways regulate the expression of PD-L1 (Li et al, 2019, Figure 4A).…”

“…MDSCs interact with CD8 + T cells via PD-L1 and inactivate CD8 + T cells by secreting TGF-β and IL-10 (Fleming et al, 2018, Figure 5A). TAMs, which are activated by IFN-γ released by CD4 + T helper cells, inactivate CD8 + T cells (Li et al, 2020, Figure 5A). Melanoma cells activate MDSCs, but inactivate CD8 + T cells via PD-L1 ( Figure 5A).…”