Lenalidomide Induces Interleukin-21 Production by T Cells and Enhances IL21-Mediated Cytotoxicity in Chronic Lymphocytic Leukemia B Cells.
Lenalidomide Induces Interleukin-21 Production by T Cells and Enhances IL21-Mediated Cytotoxicity in Chronic Lymphocytic Leukemia B Cells.
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DOI：
10.1158/2326-6066.cir-15-0291
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发表时间：
2016-08
影响因子：
10.1
通讯作者：
Byrd JC
中科院分区：
文献类型：
--
作者：
Browning RL;Byrd WH;Gupta N;Jones J;Mo X;Hertlein E;Yu L;Muthusamy N;Byrd JC
免疫调节药物来那度胺已被证明对慢性淋巴细胞白血病（CLL）患者有效，尽管在体外缺乏直接的细胞毒性作用。来那度胺体内疗效的机制被认为是通过增强免疫活性和改变肿瘤细胞-微环境相互作用的组合而发生的。我们在来自CLL患者的全血中证明来那度胺显著地消耗恶性B细胞。来那度胺还诱导来自CLL患者的T细胞中白细胞介素-21（IL 21）及其mRNA的产生。来那度胺还增强了细胞表面上功能性IL 21受体（IL 21 R）的上调，并在体外增加了受体mRNA。IL 21和来那度胺的体外组合通过多种机制增强了IL 21介导的对CLL细胞的细胞毒性。我们显示了细胞死亡与IL 21上调Bid、联合治疗增强Bid上调以及Syk和PLCG 2的Lck和下游BCR信号传导激活减弱相关。总的来说，我们证明了通过来那度胺介导的IL 21和IL 21 R诱导的免疫细胞-肿瘤细胞相互作用，以及增强的IL 21介导的细胞毒性，这为CLL患者的临床试验中的这种组合提供了理由。
The immunomodulatory drug lenalidomide has demonstrated efficacy in chronic lymphocytic leukemia (CLL) patients, despite a lack of direct cytotoxic effect in vitro. The mechanism of lenalidomide efficacy in vivo is thought to occur via a combination of enhanced immune activity and an alteration of tumor cell–microenvironment interactions. We demonstrate in whole blood from CLL patients that lenalidomide significantly depletes malignant B cells. Lenalidomide also induced production of interleukin-21 (IL21) and its mRNA in T cells from CLL patients. Lenalidomide also enhanced upregulation of functional IL21 receptor (IL21R) on the cell surface and increased receptor mRNA in vitro. The in vitro combination of IL21 and lenalidomide enhanced IL21-mediated cytotoxicity toward CLL cells through a variety of mechanisms. We show association of cell death with upregulation of Bid by IL21, enhanced upregulation of Bid by the combination therapy, and diminished Lck and downstream BCR signaling activation of Syk and PLCG2. Collectively, we demonstrated an immune cell–tumor cell interaction through lenalidomide-mediated induction of IL21 and IL21R, with enhanced IL21-mediated cytotoxicity, which provides justification for this combination in clinical trials for CLL patients.