Blocking NF-κB Is Essential for the Immunotherapeutic Effect of Recombinant IL18 in Pancreatic Cancer

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-kB pathway. Nevertheless, by coadministrating IL18 with BAY11-7082, an NF-kB 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-kB 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-kB pathway.

Pin1 promotes pancreatic cancer progression and metastasis by activation of NF‐κB‐IL‐18 feedback loop

“…IL‐18 was reported to enhance the metastatic ability of melanoma cells via the generation of ROI and activation of the MAPK pathway 42 . In agreement with our findings, other data proved that IL‐18 regulates NF‐κB signalling to implement its tumorigenic capacity, 20 which supports the Pin1/NF‐κB/IL‐18 feedback loop in pancreatic cancer cells.…”

“…Initially identified as an interferon‐γ‐inducing factor in innate and adaptive immune responses, IL‐18 has been reported to enhance Th1 immune responses 19 . However, IL‐18 is overexpressed in tumour tissues and its expression correlates with tumour progression, metastasis and poor prognosis in some cancers, such as PDAC, extranodal natural killer/T‐cell lymphoma and renal cell carcinoma 20‐22 . Evidence has suggested that IL‐18 promotes proliferation and metastasis of pancreatic cancer cell lines through the NF‐κB signalling pathway; however, when co‐administered with BAY11‐7082, an NF‐κB inhibitor, IL‐18 improved survival in a murine model of PDAC 20 …”

Hypoxia and Inflammation in Cancer, Focus on HIF and NF-κB

“…In a recent study, a combined use of IL-18 as immunotherapeutic agent alongside a targeted inhibition of the NF-κB pathway emerged as potentially effective against pancreatic cancer [188]. Recently, cancer immunotherapy effectiveness has been boosted by a better understanding of immune checkpoints.…”

Fisetin Suppresses Human Osteosarcoma U-2 OS Cell Migration and InvasionviaAffecting FAK, uPA and NF-ĸB Signaling PathwayIn Vitro

“…p-ERK1/2, and p-JNK have also been involved cell metastasis (52,53), while NF-ĸB has been linked with tumor cell metastasis (54). Inhibition of NF-ĸB has been recognized as one of the strategies to inhibit cancer cell metastasis (55). The role of uPA has also been reported to be involved in cancer cell metastasis (1) and MMPs have been shown to be up-regulated by uPA and down-regulated by TIMPs (56).…”