Lenalidomide enhances natural killer cell and monocyte-mediated antibody-dependent cellular cytotoxicity of rituximab-treated CD20+ tumor cells.
Lenalidomide enhances natural killer cell and monocyte-mediated antibody-dependent cellular cytotoxicity of rituximab-treated CD20+ tumor cells.
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DOI：
10.1158/1078-0432.ccr-07-4405
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发表时间：
2008-07-15
影响因子：
11.5
通讯作者：
Bartlett, J. Blake
中科院分区：
文献类型：
--
作者：
Wu, Lei;Adams, Mary;Bartlett, J. Blake
目的：来那度胺对骨髓增生异常综合征、多发性骨髓瘤和非霍奇金淋巴瘤 (NHL) 具有显着活性。在之前的研究中，来那度胺扩增自然杀伤（NK）细胞被证明可以增强利妥昔单抗的细胞毒作用。本研究在体外评估了来那度胺在经利妥昔单抗治疗的 NHL 细胞系和来自 B 细胞慢性淋巴细胞白血病 (B-CLL) 患者的原发性肿瘤细胞中增强抗体依赖性细胞毒性 (ADCC) 的能力。实验设计：使用体外 ADCC 系统来评估来那度胺响应利妥昔单抗增强人类 NK 细胞和单核细胞功能的能力。 结果：来那度胺通过响应 IgG 的 Fc-γ 受体介导的信号传导，直接增强 IFN-γ 的产生。对于体外多种经利妥昔单抗处理的 NHL 细胞系，它也是 NK 细胞介导和单核细胞介导的肿瘤细胞 ADCC 的有效增强剂，这种作用依赖于抗体以及白细胞介素 2 或白细胞介素 12 的存在。来那度胺还增强了 NK 细胞杀死来自三名 B-CLL 患者的原发肿瘤细胞的能力，这些患者之前曾接受过氟达拉滨加环磷酰胺治疗。增强的 NK 细胞 ADCC 与增强的颗粒酶 B 和 Fas 配体表达相关，并且可被颗粒酶 B 抑制剂抑制，并被 FasL 抗体部分抑制。增强的 NK 细胞 Fc-γ 受体信号传导与增强的磷酸化细胞外信号相关激酶水平相关，从而增强效应器功能。结论：这些研究结果表明，来那度胺有可能在体外通过 NK 细胞介导和单核细胞介导的 ADCC 机制增强利妥昔单抗诱导的 NHL 细胞系和原代 B 细胞慢性淋巴细胞白血病细胞的杀伤作用，为来那度胺与IgG1 抗体针对癌症患者的肿瘤特异性抗原。
Purpose: Lenalidomide has significant activity in myelodysplastic syndromes, multiple myeloma, and non-Hodgkin's lymphoma (NHL). In previous studies, natural killer (NK) cell expansion by lenalidomide was shown to enhance the cytotoxic effect of rituximab. This study assessed the ability of lenalidomide to enhance antibody-dependent cellular cytotoxicity (ADCC) in rituximab-treated NHL cell lines and primary tumor cells from patients with B-cell chronic lymphocytic leukemia (B-CLL) in vitro.Experimental Design: An in vitro ADCC system was used to assess the ability of lenalidomide to enhance human NK cell and monocyte function in response to rituximab.Results: Lenalidomide directly enhanced IFN-gamma production via Fc-gamma receptor-mediated signaling in response to IgG. It was also a potent enhancer of NK cell-mediated and monocyte-mediated tumor cell ADCC for a variety of rituximab-treated NHL cell lines in vitro, an effect that was dependent on the presence of antibody and either interleukin-2 or interleukin-12. Lenalidomide also enhanced the ability of NK cells to kill primary tumor cells derived from three patients with B-CLL who have been treated previously with fludarabine plus cyclophosphamide. Enhanced NK cell ADCC was associated with enhanced granzyme B and Fas ligand expression and could be inhibited by a granzyme B inhibitor and partially inhibited by antibody to FasL. Enhanced NK cell Fc-gamma receptor signaling is associated with enhanced phosphorylated extracellular signal-related kinase levels leading to enhanced effector function.Conclusions: These findings suggest that lenalidomide has the potential to enhance the rituximab-induced killing of NHL cell lines and primary B-cell chronic lymphocytic leukemia cells via a NK cell-mediated and monocyte-mediated ADCC mechanism in vitro, providing a strong rationale for the combination of lenalidomide with IgG1 antibodies to target tumor-specific antigens in patients with cancer.