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Concerted action of IFN-? and IFN-? induces local NK cell immunity and halts cancer growth.

ABSTRACT: Hepatocellular carcinoma (HCC) is the most prevalent type of liver cancer. No significant improvement has been reported with currently available systemic therapies. IFN-? has been tested in both clinic and animal models and only moderate benefits have been observed. In animal models, similar modest antitumor efficacy has also been reported for IFN-?, a new type of IFN that acts through its own receptor complex. In the present study, the antitumor efficacy of the combination of IFN-? and IFN-? was tested in the BNL mouse hepatoma model. This study was accomplished by using either engineered tumor cells (IFN-?/IFN-? gene therapy) or by directly injecting tumor-bearing mice with IFN-?/IFN-?. Both approaches demonstrated that IFN-?/IFN-? combination therapy was more efficacious than IFN monotherapy based on either IFN-? or IFN-?. In complement to tumor surgery, IFN-?/IFN-? combination induced complete tumor remission. Highest antitumor efficacy has been obtained following local administration of IFN-?/IFN-? combination at the tumor site that was associated with strong NK cells tumor infiltration. This supports the use of IFN-?/IFN-? combination as a new cancer immunotherapy for stimulating antitumor response after cancer surgery.

SUBMITTER: Lasfar A

PROVIDER: S-EPMC5226505 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Concerted action of IFN-α and IFN-λ induces local NK cell immunity and halts cancer growth.

Lasfar Ahmed A de laTorre Andrew A Abushahba Walid W Cohen-Solal Karine A KA Castaneda Ismael I Yuan Yao Y Reuhl Kenneth K Zloza Andrew A Raveche Elizabeth E Laskin Debra L DL Kotenko Sergei V SV

Oncotarget 20160801 31

Hepatocellular carcinoma (HCC) is the most prevalent type of liver cancer. No significant improvement has been reported with currently available systemic therapies. IFN-α has been tested in both clinic and animal models and only moderate benefits have been observed. In animal models, similar modest antitumor efficacy has also been reported for IFN-λ, a new type of IFN that acts through its own receptor complex. In the present study, the antitumor efficacy of the combination of IFN-α and IFN-λ wa ...[more]

PMID: 27363032

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Project description:BackgroundHCV replication in persistently infected cell culture remains resistant to IFN-α/RBV combination treatment, whereas IFN-λ1 induces viral clearance. The antiviral mechanisms by which IFN-λ1 induces sustained HCV clearance have not been determined.AimTo investigate the mechanisms by which IFN-λ clears HCV replication in an HCV cell culture model.MethodsIFN-α sensitive (S3-GFP) and resistant (R4-GFP) cells were treated with equivalent concentrations of either IFN-α or IFN-λ. The relative antiviral effects of IFN-α and IFN-λ1 were compared by measuring the HCV replication, quantification of HCV-GFP expression by flow cytometry, and viral RNA levels by real time RT-PCR. Activation of Jak-Stat signaling, interferon stimulated gene (ISG) expression, and miRNA-122 transcription in S3-GFP and R4-GFP cells were examined.ResultsWe have shown that IFN-λ1 induces HCV clearance in IFN-α resistant and sensitive replicon cell lines in a dose dependent manner through Jak-Stat signaling, and induces STAT 1 and STAT 2 activation, ISRE-luciferase promoter activation and ISG expression. Stat 3 activation is also involved in IFN-λ1 induced antiviral activity in HCV cell culture. IFN-λ1 induced Stat 3 phosphorylation reduces the expression of hepatocyte nuclear factor 4 alpha (HNF4α) through miR-24 in R4-GFP cells. Reduced expression of HNF4α is associated with decreased expression of miR-122 resulting in an anti-HCV effect. Northern blot analysis confirms that IFN-λ1 reduces miR-122 levels in R4-GFP cells. Our results indicate that IFN-λ1 activates the Stat 3-HNF4α feedback inflammatory loop to inhibit miR-122 transcription in HCV cell culture.ConclusionsIn addition to the classical Jak-Stat antiviral signaling pathway, IFN-λ1 inhibits HCV replication through the suppression of miRNA-122 transcription via an inflammatory Stat 3-HNF4α feedback loop. Inflammatory feedback circuits activated by IFNs during chronic inflammation expose non-responders to the risk of hepatocellular carcinoma.

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Concerted action of IFN-? and IFN-? induces local NK cell immunity and halts cancer growth.

Publications

Concerted action of IFN-α and IFN-λ induces local NK cell immunity and halts cancer growth.

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