Bromodomain inhibition exerts its therapeutic potential in malignant pleural mesothelioma by promoting immunogenic cell death and changing the tumor immune-environment
Bromodomain inhibition exerts its therapeutic potential in malignant pleural mesothelioma by promoting immunogenic cell death and changing the tumor immune-environment
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DOI：
10.1080/2162402x.2017.1398874
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发表时间：
2018-01-01
期刊：
影响因子：
7.2
通讯作者：
Taulli, Riccardo
中科院分区：
文献类型：
--
作者：
Riganti, Chiara;Lingua, Marcello Francesco;Taulli, Riccardo
恶性胸膜间皮瘤 (MPM) 的全身治疗对于 MPM 细胞的内在药理学耐药性及其诱导免疫抑制环境的能力具有中等活性。在这里，我们发现，与正常间皮细胞（HMC）相比，人类原代MPM细胞中溴结构域（BRD）蛋白BRD2、BRD4和BRD9的表达显着较高。纳摩尔浓度的溴结构域抑制剂 (BBI) JQ1 或 OTX015 会损害患者来源的 MPM 细胞增殖并诱导细胞周期停滞，但不影响细胞凋亡。重要的是，BBI 通过增加 ATP 和 HMGB1 的细胞外释放，并促进钙网蛋白和 ERp57 的膜暴露，引发 MPM 细胞的免疫原性细胞死亡。因此，BBI 激活树突状细胞 (DC) 介导的吞噬作用和 CD8(+) T 淋巴细胞克隆的扩增，具有抗肿瘤细胞毒性活性。 BBI 降低了 MPM 细胞中免疫检查点配体 PD-L1 的表达；而与 JQ1 处理的 MPM 细胞共培养的 CD8(+) 和 CD4(+) T 淋巴细胞均降低了 PD-1 表达，表明免疫抑制性 PD-L1/PD-1 轴受到破坏。此外，BBI 还可减少 MPM 细胞诱导的骨髓源性抑制细胞 (MDSC) 的扩增。最后，MPM的临床前模型证实，JQ1的抗肿瘤功效很大程度上是由于其通过增加肿瘤内DC和CD8(+) T淋巴细胞以及减少MDSC来恢复免疫活性环境的能力。因此，我们建议，在新药中，应研究 BBIs 用于 MPM 治疗，因为它们对肿瘤细胞和周围免疫环境的综合活性。
Systemic treatment of malignant pleural mesothelioma (MPM) is moderately active for the intrinsic pharmacological resistance of MPM cell and its ability to induce an immune suppressive environment. Here we showed that the expression of bromodomain (BRD) proteins BRD2, BRD4 and BRD9 was significantly higher in human primary MPM cells compared to normal mesothelial cells (HMC). Nanomolar concentrations of bromodomain inhibitors (BBIs) JQ1 or OTX015 impaired patient-derived MPM cell proliferation and induced cell-cycle arrest without affecting apoptosis. Importantly, BBIs primed MPM cells for immunogenic cell death, by increasing extracellular release of ATP and HMGB1, and by promoting membrane exposure of calreticulin and ERp57. Accordingly, BBIs activated dendritic cell (DC)-mediated phagocytosis and expansion of CD8(+) T-lymphocyte clones endorsed with antitumor cytotoxic activity. BBIs reduced the expression of the immune checkpoint ligand PD-L1 in MPM cells; while both CD8(+) and CD4(+) T-lymphocytes co-cultured with JQ1-treated MPM cells decreased PD-1 expression, suggesting a disruption of the immune-suppressive PD-L1/PD-1 axis. Additionally, BBIs reduced the expansion of myeloid-derived suppressor cells (MDSC) induced by MPM cells. Finally, a preclinical model of MPM confirmed that the anti-tumor efficacy of JQ1 was largely due to its ability to restore an immune-active environment, by increasing intra-tumor DC and CD8(+) T-lymphocytes, and decreasing MDSC. Thereby, we propose that, among novel drugs, BBIs should be investigated for MPM treatment for their combined activity on both tumor cells and surrounding immune-environment.