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 4

PLX51107 induces MDSC apoptosis.

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PLX51107 induces MDSC apoptosis. (A) Values represent the mean ± SEM of ...
(A) Values represent the mean ± SEM of annexin V+ MSC2 cells treated as indicated for 24 h (n = 3); P < 0.01 for DMSO versus 500 nM PLX51107 (PLX), P < 0.01 for 500 nM PLX51107 versus 500 nM PLX51107 + 25 μM Z-VAD-FMK, 2-way ANOVA model with Tukey’s correction. (B) Representative flow cytometry plot of staining from A. Annexin V+ and propidium iodide– negative early apoptosis of PLX51107-treated cells is demonstrated. (C) Murine splenic MDSCs isolated from 4T1 tumor–bearing mice treated ex vivo with media supplemented with 10 ng/mL IL-6 and GM-CSF for 48 h. Values represent the mean ± SEM of annexin V+ murine splenic MDSCs treated as indicated (n = 3); P < 0.01 for DMSO versus 500 nM PLX51107, unpaired 2-tailed Student’s t test. (D) Representative flow cytometry plot of staining from C. (E) 4T1 tumor–bearing mice were treated with control or PLX51107 (20 mg/kg) for 7 days. Splenocytes were isolated and stained for MDSCs (GR1+/CD11b+) and annexin V. Values represent fold increase of annexin V+ MDSCs in mice receiving PLX51107 compared with mice receiving control (n = 5); P < 0.01, unpaired 2-tailed Student’s t test. (F and G) CD33+/CD11b+/HLA-DRlo/– MDSCs were isolated from the peripheral blood of patients with melanoma (F) or bladder cancer (G) by FACS. Cells were cultured in human AB serum media supplemented with 10 ng/mL IL-6 and GM-CSF and treated with DMSO or 250 nM PLX51107 for 48 h. Values represent mean ± SEM of annexin V+ cells from experiments; P < 0.0001 for DMSO versus 250 nM PLX51107 in F (n = 7), and P < 0.01 for DMSO versus 250 nM PLX51107 in G (n = 3), paired 2-tailed Student’s t test. (H) Values represent mean ± SEM of cleaved caspase-3+ melanoma patient MDSCs isolated as in F and treated as indicated for 48 h (n = 3); P < 0.0001 for DMSO versus 250 nM PLX51107 and 250 nM PLX51107 versus 250 nM PLX51107 + 25 μM Z-VAD-FMK, 2-way ANOVA model with Tukey’s correction. (I) Representative flow cytometry plot of staining from H.