Lenalidomide augments actin remodeling and lowers NK-cell activation thresholds
Lenalidomide augments actin remodeling and lowers NK-cell activation thresholds
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DOI：
10.1182/blood-2015-01-625004
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发表时间：
2015-07-02
期刊：
影响因子：
20.3
通讯作者：
Davis, Daniel M.
中科院分区：
文献类型：
--
作者：
Lagrue, Kathryn;Carisey, Alex;Davis, Daniel M.
随着多发性骨髓瘤（MM）的进展，自然杀伤（NK）细胞对恶性浆细胞的反应下降。免疫调节药物来那度胺广泛用于治疗MM，但其对NK细胞生物学的影响尚不清楚。在这里，我们报告来那度胺降低了NK细胞活化的阈值，导致通过CD 16活化的50%有效浓度（EC 50）降低66%，NK 2组成员D（NKG 2D）介导的活化的EC 50降低38%，使NK细胞对较低剂量的配体产生反应。此外，来那度胺增强NK细胞应答，导致产生干扰素-γ（IFN-γ）的原代NK细胞比例增加两倍，每个细胞产生的IFN-γ量增加20倍。重要的是，来那度胺不会在未刺激的NK细胞中引发IFN-γ的产生。因此，来那度胺增强免疫应答的NK细胞臂，而不会不适当地激活NK细胞。特别具有临床意义的是，来那度胺还允许NK细胞被较低剂量的利妥昔单抗激活，利妥昔单抗是一种广泛用于治疗B细胞恶性肿瘤的抗CD 20单克隆抗体（mAb）。这支持在临床环境中联合使用来那度胺和利妥昔单抗。最后，超分辨率显微镜显示，来那度胺增加了免疫突触处皮质肌动蛋白的周期性，导致预测可穿透含有IFN-γ的囊泡的肌动蛋白网格面积增加。来自MM患者的NK细胞也以这种方式对来那度胺作出反应。这表明皮质肌动蛋白的纳米级重排，最近发现的免疫突触组装步骤，是治疗化合物的潜在新靶点。
As multiple myeloma (MM) progresses, natural killer (NK)-cell responses decline against malignant plasma cells. The immunomodulatory drug lenalidomide is widely used for treatment of MM but its influence on NK-cell biology is unclear. Here, we report that lenalidomide lowers the threshold for NK-cell activation, causing a 66% decrease in the 50% effective concentration (EC50) for activation through CD16, and a 38% decrease in EC50 for NK group 2 member D (NKG2D)-mediated activation, allowing NK cells to respond to lower doses of ligand. In addition, lenalidomide augments NK-cell responses, causing a twofold increase in the proportion of primary NK cells producing interferon-gamma (IFN-gamma), and a 20-fold increase in the amount of IFN-gamma produced per cell. Importantly, lenalidomide did not trigger IFN-gamma production in unstimulated NK cells. Thus, lenalidomide enhances the NK-cell arm of the immune response, without activating NK cells inappropriately. Of particular clinical importance, lenalidomide also allowed NK cells to be activated by lower doses of rituximab, an anti-CD20 monoclonal antibody (mAb) widely used to treat B-cell malignancies. This supports combined use of lenalidomide and rituximab in a clinical setting. Finally, superresolution microscopy revealed that lenalidomide increased the periodicity of cortical actin at immune synapses, resulting in an increase in the area of the actin mesh predicted to be penetrable to vesicles containing IFN-gamma. NK cells from MM patients also responded to lenalidomide in this way. This indicates that nanometer-scale rearrangements in cortical actin, a recently discovered step in immune synapse assembly, are a potential new target for therapeutic compounds.