<br>hIL-15 基因修饰的人自然杀伤细胞（NKL-IL15）表现出抗人白血病功能,Journal of Cancer Research and Clinical Oncology

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hIL-15 基因修饰的人自然杀伤细胞（NKL-IL15）表现出抗人白血病功能
Journal of Cancer Research and Clinical Oncology ( IF 2.7 ) Pub Date : 2018-05-08 , DOI: 10.1007/s00432-018-2654-0
Wen Jiang ₁ , Cai Zhang ₁ , Zhigang Tian ₁ , Jian Zhang ₁

Affiliation

目的自然杀伤（NK）细胞可以杀死转化的细胞，并代表抗肿瘤活性，以改善癌症的免疫治疗。在以前的工作中，我们建立了人白细胞介素 15 （hIL-15）基因修饰的 NKL 细胞（NKL-IL15），并在体外和体内证明了它们对人肝癌细胞（HCC）的有效性。为了进一步评估 NKL-IL15 细胞在人类白血病过继细胞免疫治疗中的适用性，我们在这里报告了它们在体外和体内对白血病的天然细胞毒性。方法采用流式细胞术、ELISA 和 MTT 方法进行分子表达、细胞增殖和细胞毒性测定。通过皮下注射 K562 细胞建立白血病异种移植 NOD/SCID 小鼠，然后用辐照 NKL 细胞处理。结果我们发现 NKL-IL15 细胞对人白血病细胞系和患者的原发性白血病细胞均表现出显著的高细胞溶解活性，并伴有穿孔素、颗粒酶 B 和 NKp80 等与 NK 细胞毒性相关的分子表达上调。此外，NKL-IL15 细胞分泌的细胞因子，包括 TNF-α 和 IFN-γ，可以诱导靶细胞上 NKG2D 配体的表达，从而增加白血病细胞对 NK 细胞介导的细胞溶解的敏感性。令人鼓舞的是，NKL-IL15 细胞显著抑制异种移植 NOD/SCID 小鼠白血病细胞的生长，并显著延长荷瘤小鼠的存活时间。此外，NKL-IL15 细胞对 hPBMCs 表现出刺激作用，表明 NKL-IL15 细胞处理可以改善白血病患者的免疫抑制状态。结论这些结果提供了证据，表明 IL-15 基因修饰可以增强 NK 细胞介导的抗人白血病功能，这将改善未来基于原发性 NK 细胞的白血病免疫治疗。

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hIL-15-gene modified human natural killer cells (NKL-IL15) exhibit anti-human leukemia functions

PurposeNatural killer (NK) cells can kill transformed cells and represent anti-tumor activities for improving the immunotherapy of cancer. In previous works, we established human interleukin-15 (hIL-15) gene-modified NKL cells (NKL-IL15) and demonstrated their efficiency against human hepatocarcinoma cells (HCCs) in vitro and in vivo. To further assess the applicability of NKL-IL15 cells in adoptive cellular immunotherapy for human leukemia, here we report their natural cytotoxicity against leukemia in vitro and in vivo.MethodsFlow cytometry, ELISA and MTT methods were performed for molecular expression, cell proliferation and cytotoxicity assays. Leukemia xenograft NOD/SCID mice were established by subcutaneous injection with K562 cells, and then treated with irradiated NKL cells.ResultsWe found NKL-IL15 cells displayed a significant high cytolysis activity against both human leukemia cell lines and primary leukemia cells from patients, accompanied with up-regulated expression of molecules related to NK cell cytotoxicity such as perforin, granzyme B and NKp80. Moreover, cytokines secreted by NKL-IL15 cells, including TNF-α and IFN-γ, could induce the expression of NKG2D ligands on target cells, which increased the susceptibility of leukemia cells to NK cell-mediated cytolysis. Encouragingly, NKL-IL15 cells significantly inhibited the growth of leukemia cells in xenografted NOD/SCID mice and prolonged the survival of tumor-bearing mice dramatically. Furthermore, NKL-IL15 cells displayed stimulatory effects on hPBMCs, indicating the immunesuppressive status of leukemia patients could be improved by NKL-IL15 cell treatment.ConclusionsThese results provided evidence that IL-15 gene-modification could augment NK cell-mediated anti-human leukemia function, which would improve primary NK cell-based immunotherapy for leukemia in future.

更新日期：2018-05-08

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