BET Inhibition Reverses Immune Suppression in CLL by Targeting MDSCs

A preclinical study found that targeting bromodomain and extraterminal domain epigenetic (BET) proteins—specifically BRD4—may reverse immune suppression in chronic lymphocytic leukemia (CLL) by interfering with the function of myeloid-derived suppressor cells (MDSCs). The findings support the use of BET inhibitors as a novel therapeutic strategy in CLL, a blood cancer long known for its highly immunosuppressive tumor microenvironment (TME).

Illustration of myeloid cells | Image Credit: © Sascha - stock.adobe.com

CLL is characterized by the accumulation of malignant B cells and the establishment of a TME that fosters immune dysfunction. This dysfunction arises from chronic antigen exposure, inhibitory checkpoint interactions, and immunosuppressive cytokines, which together impair T-cell activity. A key contributor to this immune suppression is the expansion and activation of MDSCs. These are immature myeloid cells reprogrammed by the TME to inhibit T-cell function through mechanisms such as arginase-1 activity, nitric oxide production, and reactive oxygen species.¹

Previous studies show that the frequency of MDSCs in the peripheral blood of patients with CLL is increased and corresponds with disease stage and progression. While several therapeutic approaches have aimed to eliminate MDSCs or block their recruitment, the most promising strategies focus on impairing their suppressive machinery.¹

This study, published in Hemato, builds on previous work demonstrating that OPN-51107 (OPN5), the BET inhibitor, reduced disease burden and altered the immune landscape in CLL mouse models. Investigators used the Eµ-TCL1 mouse model to assess how BET inhibition affects MDSC behavior. They found that MDSCs isolated from CLL-bearing mice overexpressed BRD4 and exhibited heightened immunosuppressive activity compared with their wild-type counterparts.^1,2

Treatment with OPN5, both ex vivo and in vivo, significantly reduced the immunosuppressive capacity of these MDSCs. In ex vivo assays, OPN5-treated MDSCs allowed for enhanced T-cell proliferation and interferon-gamma (IFNγ) production, 2 key markers of T-cell activation. Furthermore, in adoptive transfer experiments, in vivo treatment with OPN5 not only slowed CLL disease progression but also reshaped the immune cell populations, including a notable impact on MDSCs.¹

BET proteins, including BRD2, BRD3, and BRD4, function as epigenetic readers that regulate transcription by binding to acetylated histones and recruiting transcriptional machinery. By inhibiting BRD4 with OPN5, the study suggests that researchers can directly interfere with the transcriptional programs that equip MDSCs with immunosuppressive properties.¹

“Overall, we demonstrated that BRD4 is overexpressed in MDSCs, which may contribute to MDSC development in CLL,” the authors concluded. “Additionally, we show that pharmacological BET inhibition with OPN5 reverses MDSC-mediated immune suppression in preclinical models of CLL, highlighting the translational potential of BET inhibition as an anti-cancer therapeutic simultaneously targeting MDSCs in CLL.”¹

Taken together, the findings highlight BRD4 as a central regulator of MDSC function in CLL and suggest that pharmacological inhibition using BET inhibitors like OPN5 may offer a 2-fold benefit: directly targeting leukemia cells while also reactivating immune responses through the modulation of MDSCs. As immune evasion remains a major barrier in CLL treatment, this dual-action approach may provide a powerful, novel approach to improve patient outcomes.

REFERENCES

1. Drengler EM, Smith AL, Skupa SA, et al. BET Protein Inhibition Relieves MDSC-Mediated Immune Suppression in Chronic Lymphocytic Leukemia. Hemato. May 24, 2025. Doi:10.3390/hemato6020014

2. Smitch AL, Skupa SA, Eiken AP, et al. BET inhibition reforms the immune microenvironment and alleviates T cell dysfunction in chronic lymphocytic leukemia. JCI Insight. May 22, 2024. Doi:10.1172/jci.insight.177054.