TY - JOUR
T1 - Blocking NF-κ B is essential for the immunotherapeutic effect of recombinant IL18 in pancreatic cancer
AU - Guo, Xingjun
AU - Zheng, Lei
AU - Jiang, Jianxin
AU - Zhao, Yan
AU - Wang, Xin
AU - Shen, Ming
AU - Zhu, Feng
AU - Tian, Rui
AU - Shi, Chengjian
AU - Xu, Meng
AU - Li, Xu
AU - Peng, Feng
AU - Zhang, Hang
AU - Feng, Yechen
AU - Xie, Yu
AU - Xu, Xiaodong
AU - Jia, Wei
AU - He, Ruizhi
AU - Xie, Chencheng
AU - Hu, Jun
AU - Ye, Dawei
AU - Wang, Min
AU - Qin, Renyi
N1 - Publisher Copyright:
© 2016 AACR.
PY - 2016/12/1
Y1 - 2016/12/1
N2 - 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-κB pathway. Nevertheless, by coadministrating IL18 with BAY11-7082, an NF-κ 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 cancersuppressing functions. Although its single-agent treatment has no therapeutic effect on pancreatic cancer, when combined with the NF-κ 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-κ B pathway. Clin Cancer Res; 22(23); 5939-50.
AB - 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-κB pathway. Nevertheless, by coadministrating IL18 with BAY11-7082, an NF-κ 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 cancersuppressing functions. Although its single-agent treatment has no therapeutic effect on pancreatic cancer, when combined with the NF-κ 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-κ B pathway. Clin Cancer Res; 22(23); 5939-50.
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U2 - 10.1158/1078-0432.CCR-15-1144
DO - 10.1158/1078-0432.CCR-15-1144
M3 - Article
C2 - 27297583
AN - SCOPUS:85006256356
SN - 1078-0432
VL - 22
SP - 5939
EP - 5950
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 23
ER -