Blocking NF-κ B is essential for the immunotherapeutic effect of recombinant IL18 in pancreatic cancer

Xingjun Guo, Lei Zheng, Jianxin Jiang, Yan Zhao, Xin Wang, Ming Shen, Feng Zhu, Rui Tian, Chengjian Shi, Meng Xu, Xu Li, Feng Peng, Hang Zhang, Yechen Feng, Yu Xie, Xiaodong Xu, Wei Jia, Ruizhi He, Chencheng Xie, Jun HuDawei Ye, Min Wang, Renyi Qin

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5939-5950
Number of pages12
JournalClinical Cancer Research
Volume22
Issue number23
DOIs
StatePublished - Dec 1 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Guo, X., Zheng, L., Jiang, J., Zhao, Y., Wang, X., Shen, M., Zhu, F., Tian, R., Shi, C., Xu, M., Li, X., Peng, F., Zhang, H., Feng, Y., Xie, Y., Xu, X., Jia, W., He, R., Xie, C., ... Qin, R. (2016). Blocking NF-κ B is essential for the immunotherapeutic effect of recombinant IL18 in pancreatic cancer. Clinical Cancer Research, 22(23), 5939-5950. https://doi.org/10.1158/1078-0432.CCR-15-1144