Natural killer cell-based adoptive transfer immunotherapy for pancreatic ductal adenocarcinoma in a KrasLSL-G12D p53LSL-R172H Pdx1-Cre mouse model.
Natural killer cell-based adoptive transfer immunotherapy for pancreatic ductal adenocarcinoma in a KrasLSL-G12D p53LSL-R172H Pdx1-Cre mouse model.
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发表时间：
2019-08
影响因子：
5.3
通讯作者：
Su Hu;Jia Yang;J. Shangguan;A. Eresen;Yu Li;Q. Ma;V. Yaghmai;Yuri S. Velichko;Chunhong Hu;Zhuoli Zhang
中科院分区：
文献类型：
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作者：
Su Hu;Jia Yang;J. Shangguan;A. Eresen;Yu Li;Q. Ma;V. Yaghmai;Yuri S. Velichko;Chunhong Hu;Zhuoli Zhang
自然杀伤（NK）细胞在针对不同恶性肿瘤（包括胰腺导管腺癌（PDAC））的宿主免疫中发挥关键作用。我们的研究旨在评估基于NK细胞的过继转移免疫治疗在原位小鼠模型中对PDAC的抗肿瘤作用。使用原位KrasLSL-G12 D p53 LSL-R172 H Pdx 1-Cre（KPC）小鼠来评价治疗功效。小鼠NK细胞（LNK细胞）（1×106）静脉注射给荷瘤小鼠，每周1次，持续3周。MRI测量（肿瘤体积和表观扩散系数（ADC）值）和生存率之间的对照和LNK治疗的肿瘤进行了比较。采用流式细胞术和酶联免疫吸附试验（ELISA）分别检测LNK细胞的杀伤活性和IFN-γ水平。与脾NK细胞相比，LNK细胞在体外能产生更高水平的IFN-γ，并能更有效地裂解PDAC细胞。LNK细胞过继转移治疗引起了有效的体内抗肿瘤活性，导致KPC小鼠中肿瘤生长延迟（P=0.033）。治疗组末次ADC值为（0.94±0.06）×10-3 mm 2/s，显著高于治疗组首次ADC值（0.75±0.04）×10-3 mm 2/s，P<0.001。KPC小鼠肿瘤ADC值与对照组比较差异有统计学意义（（0.75±0.09）×10-3 mm 2/s vs（0.94±0.06）×10-3 mm 2/s，P=0.004）。我们的数据证明了基于NK细胞的过继转移免疫疗法用于PDAC治疗的潜力。
Natural killer (NK) cells play a pivotal role in host immunity against different malignancies, including pancreatic ductal adenocarcinoma (PDAC). Our study aimed to evaluate the antitumor effects of NK cell-based adoptive transfer immunotherapy for PDAC in an orthotopic mouse model. Orthotopic KrasLSL-G12D p53LSL-R172H Pdx1-Cre (KPC) mice were used to evaluate the therapeutic efficacy. Mouse NK cells (LNK cells) (1×106) were intravenously injected to tumor-bearing mice once a week for 3 weeks. MRI measurements (tumor volume and apparent diffusion coefficient (ADC) values) and survival were compared between control and LNK treated tumors. Flow cytometry and enzyme-linked immunosorbent assay (ELISA) were used to determine LNK cells cytotoxicity and IFN-γ level, respectively. LNK cells can produce a higher level of IFN-γ and more effectively lyse PDAC cells compared with spleen NK cells in vitro. LNK-cell adoptive transfer therapy elicited potent in vivo antitumor activity, resulting in delayed tumor growth (P=0.033) in KPC mice. The ADC values at the last timepoint ((0.94±0.06)×10-3 mm2/s) were significantly higher than that at first timepoint ((0.75±0.04)×10-3 mm2/s) in treated tumors (P<0.001). ADC values were significantly different between control group and treated tumors at the last time point ((0.75±0.09)×10-3 mm2/s vs (0.94±0.06)×10-3 mm2/s, P=0.004) in KPC mice. Our data demonstrate the potential of NK cell-based adoptive transfer immunotherapy for PDAC treatment.