Concerted action of IFN-α and IFN-λ 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-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 was tested in the BNL mouse hepatoma model. This study was accomplished by using either engineered tumor cells (IFN-α/IFN-λ gene therapy) or by directly injecting tumor-bearing mice with IFN-α/IFN-λ. Both approaches demonstrated that IFN-α/IFN-λ combination therapy was more efficacious than IFN monotherapy based on either IFN-α or IFN-λ. In complement to tumor surgery, IFN-α/IFN-λ combination induced complete tumor remission. Highest antitumor efficacy has been obtained following local administration of IFN-α/IFN-λ combination at the tumor site that was associated with strong NK cells tumor infiltration. This supports the use of IFN-α/IFN-λ combination as a new cancer immunotherapy for stimulating antitumor response after cancer surgery.

Association of serum interferon‐λ3 levels with hepatocarcinogenesis in chronic hepatitis C patients treated with direct‐acting antiviral agents

“…Thus, it is possible that IFN‐λ3 might be induced by such chronic inflammation, which possibly promotes NHHN and HCC development after HCV clearance. Conversely, there is another possibility that IFN‐λ3 is induced by the antitumor immune response against occult liver cancer, because some reports have shown the antitumor effect of IFN‐λ3 . Thus, although it is not known whether a higher level of IFN‐λ3 is one of the causes of liver carcinogenesis or a result of early HCC, our findings suggest that innate immune responses, including IFN‐λ3, remain after HCV eradication and such conditions could reflect the greater potential for HCC development in the background liver.…”

Genomic variability of within‐host hepatitis C variants in acute infection

“…The host IFNL3 polymorphism rs12979860 was a determinant of viral genomic variability in acute infection, and more specifically of synonymous mutations across the genome. The traditional view was that IFNL family of cytokines were mainly concerned with epithelial immunity, but recent evidence show it to modulate or influence the function of several different immune cell types such as dendritic cells, neutrophils and natural killer cells . High affinity IFNL3 binding to the receptor induces a better antiviral effect against both HBV and HCV .…”

“…The traditional view was that IFNL family of cytokines were mainly concerned with epithelial immunity, but recent evidence show it to modulate or influence the function of several different immune cell types such as dendritic cells, neutrophils and natural killer cells. 33,34 High affinity IFNL3 binding to the receptor induces a better antiviral effect against both HBV and HCV. 35 Several polymorphisms of the host IFNL3 gene have been associated with HCV clearance, although the mechanisms remain unclear.…”

Immunobiochemical reconstruction of influenza lung infection - Melanoma skin cancer interactions

“…3 shows a biochemical reaction network reconstruction customized for the case of an anti-influenza T EFF in the presence of large amounts of cognate Ag in the infected lung. In this case, the immunological complexity of interactions involving cytokines is already overwhelming (Roshani et al, 2014;Dittrich et al, 2015;Duvigneau et al, 2016;Lasfar et al, 2016;Minn and Wherry, 2016;Odenthal et al, 2016). For example, IL-2 activates and is simultaneously repressed by active Blimp-1 both directly and indirectly Collins and Henderson, 2014).…”