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Selective BET-bromodomain inhibition by JQ1 suppresses dendritic cell maturation and antigen-specific T-cell responses

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Abstract

Bromo- and extra-terminal domain (BET) inhibitors represent potential therapeutic approaches in solid and hematological malignancies that are currently analyzed in several clinical trials. Additionally, BET are involved in the epigenetic regulation of immune responses by macrophages and dendritic cells (DCs), that play a central role in the regulation of immune responses, indicating that cancer treatment with BET inhibitors can promote immunosuppressive effects. The aim of this study was to further characterize the effects of selective BET inhibition by JQ1 on DC maturation and DC-mediated antigen-specific T-cell responses. Selective BET inhibition by JQ1 impairs LPS-induced DC maturation and inhibits the migrational activity of DCs, while antigen uptake is not affected. JQ1-treated DCs show reduced ability to induce antigen-specific T-cell proliferation. Moreover, antigen-specific T cells co-cultured with JQ1-treated DCs exhibit an inactive phenotype and reduced cytokine production. JQ1-treated mice show reduced immune responses in vivo to sublethal doses of LPS, characterized by a reduced white blood cell count, an immature phenotype of splenic DCs and T cells and lower blood levels of IL-6. In our study, we demonstrate that selective BET inhibition by JQ1, a drug currently tested in clinical trials for malignant diseases, has profound effects on DC maturation and DC-mediated antigen-specific T-cell responses. These immunosuppressive effects can result in the induction of possible infectious side effects in cancer treatments. In addition, based on our results, these compounds should not be used in combinatorial regimes using immunotherapeutic approaches such as check point inhibitors, T-cell therapies, or vaccines.

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Abbreviations

BET:

Bromo- and extra-terminal domain

BMDCs:

Bone marrow-derived dendritic cells

BRD4:

Bromodomain containing protein 4

CCL:

C–C motif chemokine ligand

CCR:

C–C chemokine receptor type

CFSE:

Carboxyfluorescein succinimidyl ester

DCs:

Dendritic cells

DMSO:

Dimethyl sulfoxide

ERK:

Extracellular signal-regulated kinases

FACS:

Fluorescence-activated cell sorter

FBS:

Fetal bovine serum

FITC:

Fluorescein isothiocyanate

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

GM-CSF:

Granulocyte-macrophage colony-stimulating factor

HLA-DR:

Human leukocyte antigen DR

IL-1:

Interleukin-1

IL-10:

Interleukin-10

IL-12:

Interleukin-12

IL-4:

Interleukin-4

IL-6:

Interleukin-6

INFγ:

Interferon gamma

LPS:

Lipopolysaccharide

mAb:

Monoclonal antibody

MACS:

Magnetic cell separation

MAPK:

Mitogen-activated protein kinases

MHC:

Major histocompatibility complex

MIP-3β:

Macrophage inflammatory protein-3 beta

MoDCs:

Monocyte-derived dendritic cells

NF-κB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

OVA:

Ovalbumin

PD-L1:

Programmed cell death 1 ligand 1

RT qPCR:

Real-time quantitative polymerase chain reaction

STAT:

Signal transducer and activator of transcription

TLR:

Toll-like receptor

TNFα:

Tumor necrosis factor alpha

TNFβ:

Tumor necrosis factor beta

β-ME:

Beta-mercaptoethanol

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Funding

This study was in part supported by a scholarship awarded to Jens Nolting from Else Kröner-Fresenius-Stifung.

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Authors and Affiliations

  1. Department of Oncology, Hematology, Immuno-Oncology and Rheumatology, University Hospital of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany

    Niklas Remke, Savita Bisht, Sebastian Oberbeck, Jens Nolting & Peter Brossart

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  1. Niklas Remke
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  2. Savita Bisht
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  3. Sebastian Oberbeck
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  4. Jens Nolting
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  5. Peter Brossart
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Contributions

Conceptualization: Jens Nolting; methodology: Jens Nolting; formal analysis and investigation: Niklas Remke, Savita Bisht, and Sebastian Oberbeck; writing– original draft preparation: Niklas Remke; writing—review and editing: Jens Nolting and Peter Brossart; funding acquisition: Jens Nolting; supervision: Peter Brossart.

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Correspondence to Peter Brossart.

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The authors declare that they have no conflict of interest.

Ethical approval

Animal experiments described here comply with Directive 2010/63/EU and were approved by the government of the state of North Rhine-Westphalia. Mice were maintained according to the guidelines of the Federation of European Laboratory Animal Science Associations (FELASA). The studies were approved by the EC (131/11, 173/09).

Animal source

The strains C57BL/6-Tg(TcraTcrb)1100Mjb/Crl (OT I Mouse) and C57BL/6-Tg(TcraTcrb)425Cbn/Crl (OT II Mouse) were generously provided by J.G. van den Boorn (Dept. of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany). Each strain used in the study was originally supplied by Charles River.

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Remke, N., Bisht, S., Oberbeck, S. et al. Selective BET-bromodomain inhibition by JQ1 suppresses dendritic cell maturation and antigen-specific T-cell responses. Cancer Immunol Immunother 70, 107–121 (2021). https://doi.org/10.1007/s00262-020-02665-x

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