Antitumor activity of Type I and Type III interferons in BNL hepatoma model

Abstract

Hepatocellular carcinoma (HCC) occurs most commonly secondary to cirrhosis due to chronic hepatitis C or B virus (HCV/HBV) infections. Type I interferon (IFN-α) treatment of chronic HCV/HBV infections reduces the incidence of HCC in cirrhotic patients. However, IFN-α toxicity limits its tolerability and efficacy highlighting a need for better therapeutic treatments. A recently discovered type III IFN (IFN-λ) has been shown to possess antiviral properties against HCV and HBV in vitro. In phase I clinical trials, IFN-λ treatment did not cause significant adverse reactions. Using a gene therapy approach, we compared the antitumor properties of IFN-α and IFN-λ in a transplantable hepatoma model of HCC. BALB/c mice were inoculated with syngeneic BNL hepatoma cells, or BNL cells expressing IFN-λ (BNL.IFN-λ cells) or IFN-α (BNL.IFN-α cells). Despite the lack of antiproliferative activity of IFNs on BNL cells, both BNL.IFN-λ and BNL.IFN-α cells displayed retarded growth kinetics in vivo. Depletion of NK cells from splenocytes inhibited splenocyte-mediated cytotoxicity, demonstrating that NK cells play a role in IFN-induced antitumor responses. However, isolated NK cells did not respond directly to IFN-λ. There was also a marked NK cell infiltration in IFN-λ producing tumors. In addition, IFN-λ and, to a lesser extent, IFN-α enhanced immunocytotoxicity of splenocytes primed with irradiated BNL cells. Splenocyte cytotoxicity against BNL cells was dependent on IL-12 and IFN-λ, and mediated by dendritic cells. In contrast to NK cells, isolated from spleen CD1 1c+ and mPDCA+ dendritic cells responded directly to IFN-λ. The antitumor activities of IFN-λ against hepatoma, in combination with HCV and HBV antiviral activities warrant further investigation into the clinical use of IFN-λ to prevent HCC in HCV/HBV-infected cirrhotic patients, as well as to treat liver cancer.

Type III Interferons IL-28 and IL-29: Novel Interferon Family Members with Therapeutic Potential in Cancer Therapy

“…Abushaba et al recently reported that, using BNL hepatoma line which was resistant to IL-28A treatment due to the lack of IL-28R expression, IL-28A secreted by tumor cells reduced the tumorigenicity and retarded the growth kinetics [95]. In this tumor model, NK cells were predominant effector cells activated indirectly by IL-28A.…”

“…Recently, Abushahba et al reported that DCs are involved in type III IFN-elicited NK cell activation [95]. DCs stimulated by type III IFNs secreted more amounts of bioactive IL-12, which subsequently activated NK cells [95]. Thus, there is a possibility that type III IFN activates NK cells indirectly via stimulation of DCs.…”

“…On the other hand, in contrast to the IFN- promotion of IL-12 expression, type I IFNs can negatively regulate IL-12 expression in DCs and monocytes [101,102]. Although type III IFNs display overlapping biological activities with type I IFNs, type III IFNs may have ability to up-regulate IL-12 expression by human macrophages and mouse DCs, in contrast to type I IFNs [95,103]. Now, further analyses are needed to determine the relation between type III IFNs and IL-12 expression.…”

“…Another possible explanation of underlying mechanisms is that IL-28A, like IL-21 [94], could enhance the cytolytic activity of NK cells previously activated by stimulators such as other cytokines and chemokines, but could not induce cytotoxic activity in resting NK cells. Recently, Abushahba et al reported that DCs are involved in type III IFN-elicited NK cell activation [95]. DCs stimulated by type III IFNs secreted more amounts of bioactive IL-12, which subsequently activated NK cells [95].…”

Immunobiology of Monocytes/Macrophages in Hepatocellular Carcinoma

“…In HCC, several lines of evidence have suggest a positive role of immune system, e.g., by controlling hepatoma growth [7,[27][28][29]. Indeed, data from clinical investigations have revealed that HCC patients with an increased intratumoral accumulation of cytotoxic CD8 + T lymphocytes had a superior 5-year survival rate and a prolonged recurrence-free survival after liver resection [11,30].…”