Blocking NF-κB Is Essential for the Immunotherapeutic Effect of Recombinant IL18 in Pancreatic Cancer.
OBJECTIVE
We sought to find new immune-based treatments for pancreatic cancer.


METHODS
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-κB 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-κB 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-κB pathway. Clin Cancer Res; 22(23); 5939-50. ©2016 AACR.
Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Xingjun
X
Guo
Department of Oncology, The Sidney Kimmel Cancer Center, and the Skip Viragh Center for Pancreatic Cancer Research & Clinical Care, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Surgery, The Sidney Kimmel Cancer Center, and the Skip Viragh Center for Pancreatic Cancer Research & Clinical Care, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Lei
L
Zheng
Department of hepatic-biliary-pancreatic surgery, Renmin Hospital of Wuhan University, Wuhan, China.
Jianxin
J
Jiang
Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Yan
Y
Zhao
Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Xin
X
Wang
Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Ming
M
Shen
Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Feng
F
Zhu
Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Rui
R
Tian
Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Chengjian
C
Shi
Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Meng
M
Xu
Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Xu
X
Li
Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Feng
F
Peng
Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Hang
H
Zhang
Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Yechen
Y
Feng
Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Yu
Y
Xie
Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Xiaodong
X
Xu
Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Wei
W
Jia
Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Ruizhi
R
He
Department of Bioengineering and Therapeutic Sciences, University of Minnesota, Minneapolis, Minnesota.
Chencheng
C
Xie
Department of Colon Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
Jun
J
Hu
Department of Oncology, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Dawei
D
Ye
Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. ryqin@tjh.tjmu.edu.cn wangmin0013128@aliyun.com.
Min
M
Wang
Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. ryqin@tjh.tjmu.edu.cn wangmin0013128@aliyun.com.
Renyi
R
Qin
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D020382:Interleukin-18 / Q000276:immunology*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009570:Nitriles / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000628:therapy*; D011994:Recombinant Proteins / Q000276:immunology*; D013450:Sulfones / Q000494:pharmacology*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D023041:Xenograft Model Antitumor Assays / Q000379:methods
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D020382:Interleukin-18; D016328:NF-kappa B; D009570:Nitriles; D011994:Recombinant Proteins; D013450:Sulfones