CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Expansion of cytotoxic natural killer cells in multiple myeloma patients using K562 cells expressing OX40 ligand and membrane-bound IL-18 and IL-21.
Expansion of cytotoxic natural killer cells in multiple myeloma patients using K562 cells expressing OX40 ligand and membrane-bound IL-18 and IL-21.
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我们的数据提示，表达 OX40L、mbIL-18 和 mbIL-21 的基因工程 K562 细胞可促进 NK 细胞的扩增、增强活化信号，并增强其对 MM 细胞的细胞溶解活性。
自然杀伤（NK）细胞免疫疗法是治疗多发性骨髓瘤（MM）的有前景方法，但获得足量活化NK细胞仍具挑战。我们在此报告一种改进方法：通过基因工程改造K562细胞，使其表达OX40配体以及膜结合型（mb）IL-18和IL-21，从而在体外扩增MM患者来源的NK细胞（eNK）。
用编码mbIL-18和mbIL-21的慢病毒载体转导K562-OX40L细胞，制备K562-OX40L-mbIL-18/-21细胞，并将其作为饲养细胞；在IL-2/IL-15存在下，从健康供者（HD）和MM患者的外周血单个核细胞中扩增NK细胞。培养四周期间测定eNK细胞的纯度、扩增倍数、受体表达及功能。
短暂加入可溶性IL-18和IL-21，并与K562-OX40L细胞共同培养，可增强NK细胞扩增。NK细胞与K562-OX40L-mbIL-18/-21细胞共培养28天后，HD和MM患者来源的NK细胞分别扩增9,860倍和4,929倍。此外，eNK细胞主要活化标志物表达升高，对K562、U266和RPMI8226靶细胞的细胞毒性增强。
表达OX40L、mbIL-18和mbIL-21的基因工程K562细胞可促进NK细胞扩增、增强活化信号，并提高其对MM细胞的细胞溶解活性。
Natural killer (NK) cell-based immunotherapy is a promising treatment approach for multiple myeloma (MM), but obtaining a sufficient number of activated NK cells remains challenging. Here, we report an improved method to generate ex vivo expanded NK (eNK) cells from MM patients based on genetic engineering of K562 cells to express OX40 ligand and membrane-bound (mb) IL-18 and IL-21.
K562-OX40L-mbIL-18/-21 cells were generated by transducing K562-OX40L cells with a lentiviral vector encoding mbIL-18 and mbIL-21, and these were used as feeder cells to expand NK cells from peripheral blood mononuclear cells of healthy donors (HDs) and MM patients in the presence of IL-2/IL-15. Purity, expansion rate, receptor expression, and functions of eNK cells were determined over four weeks of culture.
NK cell expansion was enhanced by short exposure of soluble IL-18 and IL-21 with K562-OX40L cells. Co-culture of NK cells with K562-OX40L-mbIL-18/-21 cells resulted in remarkable expansion of NK cells from HDs (9,860-fold) and MM patients (4,929-fold) over the 28-day culture period. Moreover, eNK cells showed increased expression of major activation markers and enhanced cytotoxicity towards target K562, U266, and RPMI8226 cells.
Our data suggest that genetically engineered K562 cells expressing OX40L, mbIL-18, and mbIL-21 improve the expansion of NK cells, increase activation signals, and enhance their cytolytic activity towards MM cells.
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