Smits E L J M, Ponsaerts P, Van de Velde A L R, Van Driessche A, Cools N, Lenjou M, Nijs G, Van Bockstaele D R, Berneman Z N, Van Tendeloo V F I
Laboratory of Experimental Hematology, Faculty of Medicine, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium.
Leukemia. 2007 Aug;21(8):1691-9. doi: 10.1038/sj.leu.2404763. Epub 2007 May 24.
Leukemic cells exert immunosuppressive effects that interfere with dendritic cell (DC) function and hamper effective antileukemic immune responses. Here, we sought to enhance the immunogenicity of leukemic cells by loading them with the double-stranded (ds) RNA Toll-like receptor 3 (TLR3) ligand polyriboinosinic polyribocytidylic acid (poly(I:C)), mimicking viral infection of the tumor cells. Given the responsiveness of DC to TLR ligands, we hypothesized that the uptake of poly(I:C)-loaded leukemic cells by immature DC (iDC) would lead to DC activation. Primary acute myeloid leukemia (AML) cells and AML cell lines markedly responded to poly(I:C) electroporation by apoptosis, upregulation of TLR3 expression, enhanced expression of major histocompatibility complex (MHC) and costimulatory molecules and by production of type I interferons (IFN). Upon phagocytosis of poly(I:C)-electroporated AML cells, DC maturation and activation were induced as judged by an increased expression of MHC and costimulatory molecules, production of proinflammatory cytokines and an increase of T helper 1 (T(H)1)-polarizing capacity. These immune effects were suboptimal when AML cells were passively pulsed with poly(I:C), indicating the superiority of poly(I:C) transfection over pulsing. Our results demonstrate that poly(I:C) electroporation is a promising strategy to increase the immunogenicity of AML cells and to convert iDC into activated mature DC following the phagocytosis of AML cells.
白血病细胞发挥免疫抑制作用，干扰树突状细胞（DC）功能并阻碍有效的抗白血病免疫反应。在此，我们试图通过用双链（ds）RNA Toll样受体3（TLR3）配体聚肌苷酸聚胞苷酸（poly(I:C)）加载白血病细胞来增强其免疫原性，模拟肿瘤细胞的病毒感染。鉴于DC对TLR配体的反应性，我们假设未成熟DC（iDC）摄取加载了poly(I:C)的白血病细胞会导致DC活化。原发性急性髓系白血病（AML）细胞和AML细胞系对poly(I:C)电穿孔表现出明显的凋亡反应、TLR3表达上调、主要组织相容性复合体（MHC）和共刺激分子表达增强以及I型干扰素（IFN）产生。吞噬经poly(I:C)电穿孔的AML细胞后，DC成熟和活化通过MHC和共刺激分子表达增加、促炎细胞因子产生以及T辅助1（TH1）极化能力增强来判断。当AML细胞用poly(I:C)被动脉冲时，这些免疫效应并不理想，表明poly(I:C)转染优于脉冲处理。我们的结果表明，poly(I:C)电穿孔是一种有前景的策略，可增加AML细胞的免疫原性，并在AML细胞被吞噬后将iDC转化为活化的成熟DC。
