Administration of Gemcitabine After Pancreatic Tumor Resection in Mice Induces an Antitumor Immune Response Mediated by Natural Killer Cells
Administration of Gemcitabine After Pancreatic Tumor Resection in Mice Induces an Antitumor Immune Response Mediated by Natural Killer Cells
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DOI：
10.1053/j.gastro.2016.05.004
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发表时间：
2016-08-01
期刊：
影响因子：
29.4
通讯作者：
Kuehnel, Florian
中科院分区：
文献类型：
--
作者：
Guerlevik, Engin;Fleischmann-Mundt, Bettina;Kuehnel, Florian
背景与目的：即使在可能治愈的 R0 切除术后，胰腺导管腺癌 (PDAC) 患者的预后也很差，因为局部复发率和远处器官转移率很高。然而，我们没有适合手术干预的转基因动物模型。方法：为了诱导胰腺肿瘤灶的形成，我们将致癌质粒电穿孔到 LSL-KrasG12D x p53fl/fl 小鼠的胰腺中；使用睡美人转座子在 p53fl/fl 小鼠中表达突变体 Kras。我们共同递送了编码 Akt2 (myrAkt2) 组成型活性形式的转座子。检查肿瘤的癌发生和组织病理学特征。通过生物发光成像监测转移。切除肿瘤并对小鼠给予吉西他滨，并确定肿瘤复发模式和存活率。从切除部位收集免疫细胞，并通过流式细胞术和消耗实验进行分析。结果：对致癌质粒进行电穿孔后，小鼠出现了具有人类 PDAC 组织病理学特征的单个胰腺肿瘤结节。表达 myrAkt2 的胰腺肿瘤浸润周围的胰腺组织和神经元并广泛转移，反映了患者 PDAC 的侵袭性临床特征。尽管早期肿瘤切除，小鼠仍死于局部复发和远处肿瘤，但肿瘤切除后辅助给予吉西他滨延长了生存期。在给予吉西他滨辅助剂或赋形剂的小鼠中，吉西他滨显着抑制肿瘤的局部复发，但不能抑制远处器官的转移，这与临床试验中的观察结果相似。吉西他滨抑制切除边缘处 CD11b+Gr1intF4/80int 骨髓源性抑制细胞的积累，并增加该位置自然杀伤 (NK) 细胞的数量。吉西他滨介导的抗肿瘤反应需要 NK 细胞，而不是 T 细胞。结论：小鼠胰腺肿瘤切除后给予吉西他滨可激活 NK 细胞介导的抗肿瘤反应并抑制肿瘤的局部复发，这与 PDAC 患者的观察结果一致。具有可切除胰腺肿瘤的转基因小鼠可能是研究患者辅助治疗策略的有前途的工具。
BACKGROUND & AIMS: Even after potentially curative R0 resection, patients with pancreatic ductal adenocarcinoma (PDAC) have a poor prognosis owing to high rates of local recurrence and metastasis to distant organs. However, we have no suitable transgenic animal models for surgical interventions. METHODS: To induce formation of pancreatic tumor foci, we electroporated oncogenic plasmids into pancreata of LSL-KrasG12D x p53fl/fl mice; mutant Kras was expressed in p53fl/fl mice using a sleeping beauty transposon. We co-delivered a transposon encoding a constitutively active form of Akt2 (myrAkt2). Carcinogenesis and histopathologic features of tumors were examined. Metastasis was monitored by bioluminescence imaging. Tumors were resected and mice were given gemcitabine, and tumor recurrence patterns and survival were determined. Immune cells were collected from resection sites and analyzed by flow cytometry and in depletion experiments. RESULTS: After electroporation of oncogenic plasmids, mice developed a single pancreatic tumor nodule with histopathologic features of human PDAC. Pancreatic tumors that expressed myrAkt2 infiltrated the surrounding pancreatic tissue and neurons and became widely metastatic, reflecting the aggressive clinical features of PDAC in patients. Despite early tumor resection, mice died from locally recurring and distant tumors, but adjuvant administration of gemcitabine after tumor resection prolonged survival. In mice given adjuvant gemcitabine or vehicle, gemcitabine significantly inhibited local recurrence of tumors, but not metastasis to distant organs, similar to observations in clinical trials. Gemcitabine inhibited accumulation of CD11b+Gr1intF4/80int myeloid-derived suppressor cells at the resection margin and increased the number of natural killer (NK) cells at this location. NK cells but not T cells were required for gemcitabine-mediated antitumor responses. CONCLUSIONS: Gemcitabine administration after resection of pancreatic tumors in mice activates NK cell-mediated antitumor responses and inhibits local recurrence of tumors, consistent with observations from patients with PDAC. Transgenic mice with resectable pancreatic tumors might be promising tools to study adjuvant therapy strategies for patients.