Dissecting the Role of BET Bromodomain Proteins BRD2 and BRD4 in Human NK Cell Function.

Abstract

Natural killer (NK) cells are innate lymphocytes that play a pivotal role in the immune surveillance and elimination of transformed or virally infected cells. Using a chemo-genetic approach, we identify BET bromodomain containing proteins BRD2 and BRD4 as central regulators of NK cell functions, including direct cytokine secretion, NK cell contact-dependent inflammatory cytokine secretion from monocytes as well as NK cell cytolytic functions. We show that both BRD2 and BRD4 control inflammatory cytokine production in NK cells isolated from healthy volunteers and from rheumatoid arthritis patients. In contrast, knockdown of BRD4 but not of BRD2 impairs NK cell cytolytic responses, suggesting BRD4 as critical regulator of NK cell mediated tumor cell elimination. This is supported by pharmacological targeting where the first-generation pan-BET bromodomain inhibitor JQ1(+) displays anti-inflammatory effects and inhibit tumor cell eradication, while the novel bivalent BET bromodomain inhibitor AZD5153, which shows differential activity towards BET family members, does not. Given the important role of both cytokine-mediated inflammatory microenvironment and cytolytic NK cell activities in immune-oncology therapies, our findings present a compelling argument for further clinical investigation.

• Authors: Adam P Cribbs, Panagis Filippakopoulos, Martin Philpott, Graham Wells, Henry Penn, Henrik Oerum, Viia Valge-Archer, Marc Feldmann, Udo Oppermann
• Journal: Frontiers in immunology (Front Immunol) Vol. 12 Pg. 626255 ( 2021) ISSN: 1664-3224 [Electronic] Switzerland
• PMID: 33717143 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Cribbs, Filippakopoulos, Philpott, Wells, Penn, Oerum, Valge-Archer, Feldmann and Oppermann.

Chemical References

• (+)-JQ1 compound
• Azepines
• BRD2 protein, human
• BRD4 protein, human
• Cell Cycle Proteins
• Cytokines
• Heterocyclic Compounds, 2-Ring
• Piperazines
• Pyrazoles
• Pyridazines
• Transcription Factors
• Triazoles
• AZD5153

Topics

• Arthritis, Rheumatoid (genetics, metabolism)
• Azepines (pharmacology)
• Cell Cycle Proteins (antagonists & inhibitors, genetics, metabolism)
• Cytokines
• Healthy Volunteers
• Heterocyclic Compounds, 2-Ring (pharmacology)
• High-Throughput Nucleotide Sequencing
• Humans
• Inflammation (metabolism)
• Killer Cells, Natural (drug effects, metabolism)
• Piperazines (pharmacology)
• Pyrazoles (pharmacology)
• Pyridazines (pharmacology)
• Transcription Factors (antagonists & inhibitors, genetics, metabolism)
• Transcriptome
• Triazoles (pharmacology)