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

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2021 Mar 15

PMID 33717143

Citations 11

Authors

Adam P Cribbs

Panagis Filippakopoulos

Martin Philpott

Graham Wells

Henry Penn

Henrik Oerum

Viia Valge-Archer

Marc Feldmann

Udo Oppermann

Affiliations

Soon will be listed here.

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.

Citing Articles

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BET inhibitors drive Natural Killer activation in non-small cell lung cancer via BRD4 and SMAD3.

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