Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA, USA.
Sci Rep. 2017 Oct 31;7(1):14684. doi: 10.1038/s41598-017-14661-w.
Exosomes, small (30-150 nm) extracellular vesicles (EVs) isolated from plasma of patients with acute myeloid leukemia (AML) carry leukemia-associated antigens and multiple inhibitory molecules. Circulating exosomes can deliver suppressive cargos to immune recipient cells, inhibiting anti-tumor activities. Pre-therapy plasma of refractory/relapsed AML patients contains elevated levels of immunosuppressive exosomes which interfere with anti-leukemia functions of activated immune cells. We show that exosomes isolated from pre-therapy plasma of the AML patients receiving adoptive NK-92 cell therapy block anti-leukemia cytotoxicity of NK-92 cells and other NK-92 cell functions. NK-92 cells do not internalize AML exosomes. Instead, signaling via surface receptors expressed on NK-92 cells, AML exosomes simultaneously deliver multiple inhibitory ligands to the cognate receptors. The signals are processed downstream and activate multiple suppressive pathways in NK-92 cells. AML exosomes reprogram NK-92 cells, interfering with their anti-leukemia functions and reducing the therapeutic potential of adoptive cell transfers. Plasma-derived exosomes interfere with immune cells used for adoptive cell therapy and may limit expected therapeutic benefits of adoptive cell therapy.
外泌体是从急性髓系白血病（AML）患者血浆中分离出来的小（30-150nm）细胞外囊泡（EVs），携带白血病相关抗原和多种抑制分子。循环外泌体可以向免疫受体细胞传递抑制性货物，抑制抗肿瘤活性。难治/复发 AML 患者的治疗前血浆中含有高水平的免疫抑制性外泌体，干扰活化免疫细胞的抗白血病功能。我们表明，接受过继 NK-92 细胞治疗的 AML 患者治疗前血浆中分离的外泌体阻断 NK-92 细胞的抗白血病细胞毒性和其他 NK-92 细胞功能。NK-92 细胞不会内化 AML 外泌体。相反，AML 外泌体通过 NK-92 细胞表面表达的受体发出信号，同时将多种抑制性配体递送到同源受体。信号在下游进行处理，并在 NK-92 细胞中激活多种抑制途径。AML 外泌体重新编程 NK-92 细胞，干扰其抗白血病功能，并降低过继细胞转移的治疗潜力。血浆衍生的外泌体干扰用于过继细胞治疗的免疫细胞，可能限制过继细胞治疗的预期治疗益处。
