Blocking NF-κB Is Essential for the Immunotherapeutic Effect of Recombinant IL18 in Pancreatic Cancer
Blocking NF-κB Is Essential for the Immunotherapeutic Effect of Recombinant IL18 in Pancreatic Cancer
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DOI：
10.1158/1078-0432.ccr-15-1144
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发表时间：
2016-12-01
影响因子：
11.5
通讯作者：
Qin, Renyi
中科院分区：
文献类型：
--
作者：
Guo, Xingjun;Zheng, Lei;Qin, Renyi
目的：实验设计：我们检测胰腺癌患者血浆和标本中IL 18的表达。然后，我们研究了IL 18是否有治疗效果的胰腺癌在体外和体内和任何潜在的mechanism.Results：较高的血浆IL 18与较长的总生存期（OS），但较高的IL 18在胰腺癌组织中与较短的OS和增加浸润和转移。单独的重组IL 18在具有原位移植肿瘤的同基因小鼠中没有抗肿瘤作用，并且在免疫功能低下的小鼠中促进肿瘤;它还通过增强外周血和淋巴结中的细胞毒性T细胞和NK细胞的活性来促进体外和体内的免疫应答。然而，IL 18通过NF-κ B B通路促进胰腺癌细胞的增殖和侵袭，在体外和体内。IL 18与NF-κ B B抑制剂BAY 11 -7082联合应用，可预防IL 18的癌前效应，延长小鼠生存期。虽然其单一药物治疗对胰腺癌没有治疗效果，但当与NF-κ B通路抑制剂组合时，IL 18改善了鼠胰腺癌模型中的存活率。我们的研究暗示了使用IL 18和靶向NF-κ B通路的组合免疫疗法的可能性。(C)2016年AACR。
Purpose: We sought to find new immune-based treatments for pancreatic cancer.Experimental Design: We detected IL18 expression in plasma and specimens from patients with pancreatic cancer. We then investigated whether IL18 had a therapeutic effect for pancreatic cancer in vitro and in vivo and any underlying mechanisms.Results: Higher plasma IL18 was associated with longer overall survival (OS), but higher IL18 in pancreatic cancer tissues was associated with shorter OS and increased invasion and metastasis. Recombinant IL18 alone had no antitumor effect in the syngeneic mice with orthotopically transplanted tumors and promoted tumors in immunocompromised mice; it also facilitated immune responses in vitro and in vivo by augmenting the activity of cytotoxic T cells and NK cells in peripheral blood and lymph nodes. However, IL18 promoted the proliferation and invasion of pancreatic cancer cells, in vitro and in vivo, through the NF-kappa B pathway. Nevertheless, by coadministrating IL18 with BAY11-7082, an NF-kappa B inhibitor, we were able to prevent the procancerous effects of IL18 and prolong the survival time of the mice.Conclusions: IL18 has both cancer-promoting and cancer-suppressing functions. Although its single-agent treatment has no therapeutic effect on pancreatic cancer, when combined with the NF-kappa B pathway inhibitor, IL18 improved survival in a murine pancreatic cancer model. Our study implies the possibility of a combinational immunotherapy that uses IL18 and targets NF-kappa B pathway. (C) 2016 AACR.