BRD4 inhibition leads to MDSC apoptosis and enhances checkpoint blockade therapy
Himanshu Savardekar, … , Kari L. Kendra, William E. Carson III
Himanshu Savardekar, … , Kari L. Kendra, William E. Carson III
Published August 5, 2025
Citation Information: J Clin Invest. 2025;135(19):e181975. https://doi.org/10.1172/JCI181975.
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Research Article Immunology Oncology

BRD4 inhibition leads to MDSC apoptosis and enhances checkpoint blockade therapy

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 antitumor 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 (MDSCs) 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 MDSCs 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 MDSCs. BRD4 inhibition enhanced anti–PD-L1 therapy in the EMT6, 4T1, and Lewis lung carcinoma 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.

Authors

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

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Figure 6

PLX51107 enhances the efficacy of anti–PD-L1 immune checkpoint therapy.

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PLX51107 enhances the efficacy of anti–PD-L1 immune checkpoint therapy. ...
(A and B) Frequency of intratumoral CD45+CD3+CD25+ (A) and CD45+CD3+CD69+ cells (B) analyzed by flow cytometry in EMT6 tumor–bearing mice treated for 1 week with control or PLX51107 (PLX). Values represent mean ± SEM; CD25: P < 0.01, n = 8–9 and CD69: P < 0.05, n = 5, unpaired 2-tailed Student’s t test. (C) EMT6 tumor–bearing mice were treated with control (vehicle and IgG), 20 mg/kg PLX51107 daily, 100 μg anti–PD-L1 3 times a week, or PLX51107 + anti–PD-L1. Tumor volumes were measured 3 times a week with digital calipers. Values are the mean ± SEM of tumor volumes at each time point (n = 5); P < 0.01 for combination versus PLX51107 and combination versus anti–PD-L1 (linear mixed model with Tukey-Kramer adjustment). (D) EMT6 tumor–bearing mice were treated as in C. Treatment was administered for 60 days or until institutional removal criteria were met, at which point treatment was stopped. Survival analyzed by 1-way ANOVA with Tukey’s correction; P < 0.05, n = 11. Long-term treatment did not elicit discernible toxicity. (E–G) The 4T1 tumor–bearing mice were treated as described in A. Values represent mean ± SEM of tumor volumes at each time point. Combination versus PLX51107 and combination versus anti–PD-L1; P < 0.01, linear mixed model with Tukey-Kramer adjustment. (F) Spider plot of tumor growth curves in E. (G) Images of 4T1 tumors at day 16. (H) 4T1 tumors were processed into single-cell suspensions. Values represent mean ± SEM of GR1+/CD11b+ MDSCs within the CD45+ population; P < 0.001 for control versus PLX51107, and P = 0.012 for anti–PD-L1 versus combination (Combo) treatment (1-way ANOVA with Tukey’s correction). (I) The 4T1 tumor–bearing mice were treated with control (vehicle and IgG), 20 mg/kg PLX51107 daily, 200 μg anti–LAG-3 3 times a week, or PLX51107 + anti–LAG-3. Tumor volumes were measured as in C. Values represent mean ± SEM of tumor volumes at each time point. Combination versus PLX51107: P < 0.05, n = 5; combination versus anti–LAG-3: P < 0.05, n = 5, linear mixed model with Tukey-Kramer adjustment, test results averaged over all days. *P < 0.05 and **P < 0.01.