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ResearchIn-Press PreviewImmunologyOncology Open Access | 10.1172/JCI181975

BRD4 inhibition leads to MDSC apoptosis and enhances checkpoint blockade therapy

Himanshu Savardekar,1 Andrew Stiff,1 Alvin Liu,1 Robert Wesolowski,1 Emily Schwarz,1 Ian C. Garbarine,1 Megan C. Duggan,1 Sara Zelinskas,1 Jianying Li,1 Gabriella Lapurga,1 Alexander Abreo,1 Lohith Savardekar,1 Ryan Parker,1 Julia Sabella,1 Mallory J. DiVincenzo,1 Brooke Benner,1 Steven H. Sun,1 Dionisia Quiroga,1 Luke Scarberry,1 Gang Xin,1 Anup Dey,2 Keiko Ozato,2 Lianbo Yu,3 Merve Hasanov,1 Debasish Sundi,1 Richard C. Wu,1 Kari L. Kendra,1 and William E. Carson III1

1The Ohio State University Comprehensive Cancer Center, Columbus, United States of America

2Division of Developmental Biology, National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

3Department of Biomedical Informatics, The Ohio State University, Columbus, United States of America

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1The Ohio State University Comprehensive Cancer Center, Columbus, United States of America

2Division of Developmental Biology, National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

3Department of Biomedical Informatics, The Ohio State University, Columbus, United States of America

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1The Ohio State University Comprehensive Cancer Center, Columbus, United States of America

2Division of Developmental Biology, National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

3Department of Biomedical Informatics, The Ohio State University, Columbus, United States of America

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1The Ohio State University Comprehensive Cancer Center, Columbus, United States of America

2Division of Developmental Biology, National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

3Department of Biomedical Informatics, The Ohio State University, Columbus, United States of America

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1The Ohio State University Comprehensive Cancer Center, Columbus, United States of America

2Division of Developmental Biology, National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

3Department of Biomedical Informatics, The Ohio State University, Columbus, United States of America

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1The Ohio State University Comprehensive Cancer Center, Columbus, United States of America

2Division of Developmental Biology, National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

3Department of Biomedical Informatics, The Ohio State University, Columbus, United States of America

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1The Ohio State University Comprehensive Cancer Center, Columbus, United States of America

2Division of Developmental Biology, National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

3Department of Biomedical Informatics, The Ohio State University, Columbus, United States of America

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1The Ohio State University Comprehensive Cancer Center, Columbus, United States of America

2Division of Developmental Biology, National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

3Department of Biomedical Informatics, The Ohio State University, Columbus, United States of America

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1The Ohio State University Comprehensive Cancer Center, Columbus, United States of America

2Division of Developmental Biology, National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

3Department of Biomedical Informatics, The Ohio State University, Columbus, United States of America

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1The Ohio State University Comprehensive Cancer Center, Columbus, United States of America

2Division of Developmental Biology, National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

3Department of Biomedical Informatics, The Ohio State University, Columbus, United States of America

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1The Ohio State University Comprehensive Cancer Center, Columbus, United States of America

2Division of Developmental Biology, National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

3Department of Biomedical Informatics, The Ohio State University, Columbus, United States of America

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1The Ohio State University Comprehensive Cancer Center, Columbus, United States of America

2Division of Developmental Biology, National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

3Department of Biomedical Informatics, The Ohio State University, Columbus, United States of America

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1The Ohio State University Comprehensive Cancer Center, Columbus, United States of America

2Division of Developmental Biology, National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

3Department of Biomedical Informatics, The Ohio State University, Columbus, United States of America

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1The Ohio State University Comprehensive Cancer Center, Columbus, United States of America

2Division of Developmental Biology, National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

3Department of Biomedical Informatics, The Ohio State University, Columbus, United States of America

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1The Ohio State University Comprehensive Cancer Center, Columbus, United States of America

2Division of Developmental Biology, National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

3Department of Biomedical Informatics, The Ohio State University, Columbus, United States of America

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1The Ohio State University Comprehensive Cancer Center, Columbus, United States of America

2Division of Developmental Biology, National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

3Department of Biomedical Informatics, The Ohio State University, Columbus, United States of America

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1The Ohio State University Comprehensive Cancer Center, Columbus, United States of America

2Division of Developmental Biology, National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

3Department of Biomedical Informatics, The Ohio State University, Columbus, United States of America

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1The Ohio State University Comprehensive Cancer Center, Columbus, United States of America

2Division of Developmental Biology, National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

3Department of Biomedical Informatics, The Ohio State University, Columbus, United States of America

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1The Ohio State University Comprehensive Cancer Center, Columbus, United States of America

2Division of Developmental Biology, National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

3Department of Biomedical Informatics, The Ohio State University, Columbus, United States of America

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1The Ohio State University Comprehensive Cancer Center, Columbus, United States of America

2Division of Developmental Biology, National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

3Department of Biomedical Informatics, The Ohio State University, Columbus, United States of America

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1The Ohio State University Comprehensive Cancer Center, Columbus, United States of America

2Division of Developmental Biology, National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

3Department of Biomedical Informatics, The Ohio State University, Columbus, United States of America

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1The Ohio State University Comprehensive Cancer Center, Columbus, United States of America

2Division of Developmental Biology, National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

3Department of Biomedical Informatics, The Ohio State University, Columbus, United States of America

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1The Ohio State University Comprehensive Cancer Center, Columbus, United States of America

2Division of Developmental Biology, National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

3Department of Biomedical Informatics, The Ohio State University, Columbus, United States of America

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1The Ohio State University Comprehensive Cancer Center, Columbus, United States of America

2Division of Developmental Biology, National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

3Department of Biomedical Informatics, The Ohio State University, Columbus, United States of America

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1The Ohio State University Comprehensive Cancer Center, Columbus, United States of America

2Division of Developmental Biology, National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

3Department of Biomedical Informatics, The Ohio State University, Columbus, United States of America

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1The Ohio State University Comprehensive Cancer Center, Columbus, United States of America

2Division of Developmental Biology, National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

3Department of Biomedical Informatics, The Ohio State University, Columbus, United States of America

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1The Ohio State University Comprehensive Cancer Center, Columbus, United States of America

2Division of Developmental Biology, National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

3Department of Biomedical Informatics, The Ohio State University, Columbus, United States of America

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1The Ohio State University Comprehensive Cancer Center, Columbus, United States of America

2Division of Developmental Biology, National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

3Department of Biomedical Informatics, The Ohio State University, Columbus, United States of America

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Published August 5, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI181975.
Copyright © 2025, Savardekar et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published August 5, 2025 - Version history
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Abstract

BRD4 is an epigenetic reader protein that regulates oncogenes such as myc in cancer. However, its additional role in shaping immune responses via regulation of inflammatory and myeloid cell responses is not yet fully understood. This work further characterized the multifaceted role of BRD4 in anti-tumor immunity. NanoString gene expression analysis of EMT6 tumors treated with a BRD4 inhibitor identified a reduction in myeloid gene expression signatures. Additionally, BRD4 inhibition significantly reduced myeloid derived suppressor cells (MDSC) in the spleens and tumors of mice in multiple tumor models and also decreased the release of tumor-derived MDSC growth and chemotactic factors. Pharmacologic inhibition of BRD4 in MDSC induced apoptosis and modulated expression of apoptosis regulatory proteins. A BRD4-myeloid specific knockout model suggested that the dominant mechanism of MDSC reduction after BRD4 inhibition was primarily through a direct effect on MDSC. BRD4 inhibition enhanced anti-PD-L1 therapy in the EMT6, 4T1, and LLC tumor models, and the efficacy of the combination treatment was dependent on CD8+ T cells and on BRD4 expression in the myeloid compartment. These results identify BRD4 as a regulator of MDSC survival and provide evidence to further investigate BRD4 inhibitors in combination with immune based therapies.

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  • Version 1 (August 5, 2025): In-Press Preview
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