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Blocking NF-κB Is Essential for the Immunotherapeutic Effect of Recombinant IL18 in Pancreatic Cancer
- Source :
- Clinical Cancer Research. 22:5939-5950
- Publication Year :
- 2016
- Publisher :
- American Association for Cancer Research (AACR), 2016.
-
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-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.
- Subjects :
- 0301 basic medicine
Cancer Research
medicine.medical_treatment
Metastasis
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Immune system
In vivo
Cell Line, Tumor
Pancreatic cancer
Nitriles
medicine
Animals
Humans
Cytotoxic T cell
Sulfones
Cell Proliferation
Mice, Inbred BALB C
business.industry
Interleukin-18
NF-kappa B
Cancer
NF-κB
Immunotherapy
medicine.disease
Xenograft Model Antitumor Assays
Recombinant Proteins
Killer Cells, Natural
Mice, Inbred C57BL
Pancreatic Neoplasms
030104 developmental biology
Oncology
chemistry
030220 oncology & carcinogenesis
Immunology
Cancer research
Female
business
T-Lymphocytes, Cytotoxic
Subjects
Details
- ISSN :
- 15573265 and 10780432
- Volume :
- 22
- Database :
- OpenAIRE
- Journal :
- Clinical Cancer Research
- Accession number :
- edsair.doi.dedup.....e036b527e2b5c5fb6150a7a599cf9124