Drengler Erin M, Smith Audrey L, Skupa Sydney A, Schmitz Elizabeth, Mohamed Eslam, El-Gamal Dalia
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.
College of Medicine and College of Graduate Studies, California Northstate University, Elk Grove, CA 95757, USA.
Hemato. 2025 Jun;6(2). doi: 10.3390/hemato6020014. Epub 2025 May 24.
Myeloid-derived suppressor cells (MDSCs) contribute to immune suppression observed in chronic lymphocytic leukemia (CLL). MDSCs are immature myeloid cells that are hijacked during development and further reprogrammed by the tumor microenvironment (TME) to harbor immune-suppressive properties and inhibit T-cell functions. Bromodomain and extraterminal domain (BET) proteins, including BRD4, are epigenetic modulators that regulate genes implicated in CLL pathogenesis and TME interactions. Previously, we investigated how the novel BET inhibitor OPN-51107 (OPN5) prevents CLL disease expansion, modulates T-cell immune function, and alters gene expression related to MDSCs. In turn, we hypothesize that BET proteins such as BRD4 regulate MDSC functions, and subsequent pharmacological inhibition of BRD4 will alleviate MDSC-mediated immune suppression in CLL.
Utilizing the Eμ-TCL1 mouse model of CLL, we evaluated BRD4 protein expression in MDSCs derived from the bone marrow of transgenic and age-matched wild-type (WT) mice. We then investigated the ex vivo functionality of OPN5-treated MDSCs, expanded from Eμ-TCL1 and WT bone marrow in MDSC-supportive medium. Finally, we conducted an in vivo study utilizing the Eμ-TCL1 adoptive transfer mouse model to determine the in vivo effects of OPN5 on MDSCs and other immune populations.
Through the course of this study, we found that MDSCs isolated from Eμ-TCL1 mice upregulate BRD4 expression and are more immune-suppressive than their WT counterparts. Furthermore, we demonstrated ex vivo OPN5 treatment reverses the immune-suppressive capacity of MDSCs isolated from leukemic mice, evident via enhanced T-cell proliferation and IFNγ production. Finally, we showed in vivo OPN5 treatment slows CLL disease progression and modulates immune cell populations, including MDSCs.
Altogether, these data support BET inhibition as a useful therapeutic approach to reverse MDSC-mediated immune suppression in CLL.
髓系来源的抑制性细胞（MDSCs）促成了慢性淋巴细胞白血病（CLL）中观察到的免疫抑制。MDSCs是未成熟的髓系细胞，在发育过程中被劫持，并被肿瘤微环境（TME）进一步重编程，以具有免疫抑制特性并抑制T细胞功能。包括BRD4在内的溴结构域和额外末端结构域（BET）蛋白是表观遗传调节剂，可调节与CLL发病机制和TME相互作用相关的基因。此前，我们研究了新型BET抑制剂OPN-51107（OPN5）如何阻止CLL疾病进展、调节T细胞免疫功能以及改变与MDSCs相关的基因表达。相应地，我们推测诸如BRD4之类的BET蛋白调节MDSCs的功能，随后对BRD4进行药理学抑制将减轻CLL中MDSCs介导的免疫抑制。
利用CLL的Eμ-TCL1小鼠模型，我们评估了从转基因和年龄匹配的野生型（WT）小鼠骨髓中分离出的MDSCs中BRD4蛋白的表达。然后，我们研究了在MDSC支持培养基中从Eμ-TCL1和WT骨髓扩增的经OPN5处理的MDSCs的体外功能。最后，我们利用Eμ-TCL1过继转移小鼠模型进行了一项体内研究，以确定OPN5对MDSCs和其他免疫细胞群的体内作用。
在本研究过程中，我们发现从Eμ-TCL1小鼠分离出的MDSCs上调了BRD4表达，并且比野生型对应物具有更强的免疫抑制作用。此外，我们证明体外OPN5处理可逆转从白血病小鼠分离出的MDSCs的免疫抑制能力，这通过增强T细胞增殖和IFNγ产生得以体现。最后，我们表明体内OPN5处理可减缓CLL疾病进展并调节免疫细胞群，包括MDSCs。
总之，这些数据支持BET抑制作为一种有用的治疗方法，可逆转CLL中MDSCs介导的免疫抑制。
