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 1

Nanostring pan-cancer immune profiling identifies reduced myeloid cell infiltration of EMT6 tumors treated with PLX51107.

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Nanostring pan-cancer immune profiling identifies reduced myeloid cell i...
(A–H) BALB/c mice were inoculated with 1 × 106 EMT6 cells and treated with vehicle (control) or 20 mg/kg PLX51107 (PLX) daily p.o. once tumors were palpable (50 mm3). After 1 week of treatment, RNA was extracted from whole tumors. Gene expression was then analyzed using the nCounter PanCancer Immune Profiling Panel. Raw cell abundance scores for indicated cell types are displayed on a logarithmic scale. A difference in the mean raw abundance score of 1 between control and PLX51107 treatments indicates a 2-fold difference. ANOVA models and t statistics were used for the comparison of cell type scores (log2) between control and PLX51107. (I) Pan-cancer BRD4 tumor gene expression association with gene signatures of suppressive cell types. Expression signatures were part of the TIDE algorithm. z > 0 represents a positive association. (J–N) BALB/c mice were inoculated with 1 × 105 4T1 cells and treated with vehicle (control) or 20 mg/kg PLX51107 daily p.o. once tumors were palpable (50 mm3). After 8 days of treatment, tumors were processed into single-cell suspensions and stained with fluorescent antibodies. Cell populations were acquired by spectral flow cytometry, unmixed on the Cytek Aurora 5L cytometer, and processed using the OMIQ software platform. (O and P) EMT6 tumors from mice treated as in A were fixed and stained with an antibody against F4/80 (O) or GR1 (P) and visualized using an HRP-conjugated secondary antibody. ImageJ software was used to count HRP+ cells from 5 high-powered fields per slide to obtain an average number of positive cells. The bar graph represents the mean ± SEM of GR1+ cells from 6 slides per treatment group; P < 0.05 (unpaired 2-tailed Student’s t test). (Q and R) Representative images of GR1+ cells labeled with black arrows in tumors of control (P) or PLX51107-treated (O) EMT6 tumor–bearing mice. Scale bar: 20 μm. (S and T) TIMER2 analysis of tumor BRD4 expression (S) or tumor MDSC gene signature expression (T) in The Cancer Genome Atlas breast cancer patients at different stages (n = 1,100). Values on the bar graph are z scores with the Cox proportional hazard model to evaluate significance. z > 0 indicates a positive association. MDSC gene signature expression was quantified using the TIDE algorithm.