Genetically re-engineered K562 cells significantly expand and functionally activate cord blood natural killer cells: Potential for adoptive cellular immunotherapy
Genetically re-engineered K562 cells significantly expand and functionally activate cord blood natural killer cells: Potential for adoptive cellular immunotherapy
复制标题
DOI：
10.1016/j.exphem.2016.10.003
复制
发表时间：
2017-02-01
影响因子：
2.6
通讯作者：
Cairo, Mitchell S.
中科院分区：
文献类型：
--
作者：
Ayello, Janet;Hochberg, Jessica;Cairo, Mitchell S.
自然杀伤（NK）细胞在减少同种异体干细胞移植后血液系统恶性肿瘤患者的复发中发挥着重要作用，但NK细胞的数量和自然产生的抑制信号限制了它们的能力。白细胞介素-15 （IL-15）和4-1BBL是NK细胞扩增和功能激活的重要调节剂。为了克服这些限制，我们用转基因K562- mbil15 - 41bbl （MODK562）或野生型K562 （WTK562）体外扩增脐带血单核细胞（cbmncs） 7天。NK细胞扩增；溶酶体相关膜蛋白-1 （LAMP-1）、颗粒酶B和穿孔素的表达；体外和体内对b细胞非霍奇金淋巴瘤（B-NHL）的细胞毒性进行了评价。通过肿瘤体积、细胞数量和存活监测b - nhl异种移植非肥胖糖尿病严重联合免疫缺陷(NOD-scid) γ (NSG)小鼠体内肿瘤生长情况。与WTK562相比，MODK562培养的CB MNCs的NK扩增量显著增加（35倍，p < 0.05）；LAMP-1 （p < 0.05）、颗粒酶B、穿孔素表达（p < 0.001）；体外抗B-NHL细胞毒性（p < 0.01）。与WTK562相比，经MODK562 CB处理的异种移植小鼠在5周时B-NHL肿瘤体积（p = 0.0086）和B-NHL细胞数量（p < 0.01）显著减少，10周时存活率显著提高（p < 0.001）。综上所述，MODK562显著增强了人Burkitt淋巴瘤异种移植NSG模型中CB NK的扩增和细胞毒性，提高了患者的存活率，未来可作为脐带CB移植后的过继细胞免疫治疗。未来的发展方向包括扩展抗cd20嵌合受体修饰的CB NK细胞以增强体内和体外靶向B-NHL。版权所有2016 ISEH -国际实验血液学学会Elsevier Inc.出版。
Natural killer (NK) cells play a significant role in reducing relapse in patients with hematological malignancies after allogeneic stem cell transplantation, but NK cell number and naturally occurring inhibitory signals limit their capability. Interleukin-15 (IL-15) and 4-1BBL are important modulators of NK expansion and functional activation. To overcome these limitations, cord blood mononuclear cells (CB MNCs) were ex vivo expanded for 7 days with genetically modified K562-mbIL15-41BBL (MODK562) or wild-type K562 (WTK562). NK cell expansion; expression of lysosome-associated membrane protein-1 (LAMP-1), granzyme B, and perforin; and in vitro and in vivo cytotoxicity against B-cell non-Hodgkin lymphoma (B-NHL) were evaluated. In vivo tumor growth in B-NHL-xenografted nonobese diabetic severe combined immune deficient (NOD-scid) gamma (NSG) mice was monitored by tumor volume, cell number, and survival. CB MNCs cultured with MODK562 compared with WTK562 demonstrated significantly increased NK expansion (thirty-fivefold, p < 0.05); LAMP-1 (p < 0.05), granzyme B, and perforin expression (p < 0.001); and in vitro cytotoxicity against B-NHL (p < 0.01). Xenografted mice treated with MODK562 CB experienced significantly decreased B-NHL tumor volume (p = 0.0086) and B-NHL cell numbers (p < 0.01) at 5 weeks and significantly increased survival (p < 0.001) at 10 weeks compared with WTK562. In summary, MODK562 significantly enhanced CB NK expansion and cytotoxicity, enhanced survival in a human Burkitt's lymphoma xenograft NSG model, and could be used in the future as adoptive cellular immunotherapy after umbilical CB transplantation. Future directions include expanding anti-CD20 chimeric receptor-modified CB NK cells to enhance B-NHL targeting in vitro and in vivo. Copyright (C) 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc.