Antitumor Activity of IFN-λ in Murine Tumor Models

Abstract

IFN-λ 1, -λ 2 and -λ 3 have been discovered as the latest members of the class II cytokine family and shown to possess antiviral activity. Murine B16 melanoma and Colon26 cancer cells were transduced with mouse IFN-λ to determine whether IFN-λ possesses antitumor activity. Overexpression of IFN-λ induced cell surface MHC class I expression and Fas/CD95 Ag, induced significant caspase-3/7 activity, and increased p21Waf1/Cip1 and dephosphorylated Rb (Ser780) in B16 cells in vitro. IFN-λ expression in tumor cell lines markedly inhibited s.c. and metastatic tumor formation in vivo compared with mock transfections (p < 0.05). Moreover, IFN-λ expression induced lymphocytic infiltrates, and an Ab-mediated immune cell depletion assay showed that NK cells were critical to IFN-λ-mediated tumor growth inhibition. Hydrodynamic injection of IFN-λ cDNA successfully targeted liver metastatic foci of Colon26 cells, and moderately decreased the mortality of mice with tumors. IFN-λ overexpression in the liver increased NK/NKT cells and enhanced their tumor-killing activity, and suggested the activation of innate immune responses. Thus, IFN-λ induced both tumor apoptosis and NK cell-mediated immunological tumor destruction through innate immune responses. These findings suggested that local delivery of IFN-λ might prove a useful adjunctive strategy in the clinical treatment of human malignancies.

An Important Role for Type III Interferon (IFN-λ/IL-28) in TLR-Induced Antiviral Activity

“…We confirmed the broad expression pattern of the IFNAR system, and found that among the cell types examined, that pDCs were the only hemopoietic cell type that responded to IFN-. Others have reported that human monocytes, blood monocyte-derived DCs, and murine intrahepatic CD3 Ϫ DX5 ϩ NK cells respond to IFN-or express the receptor chains (28,29,47,49). Therefore, we conclude that only few cell types of the hemopoietic compartment are responsive to IFN-, although we cannot exclude that expression of the type III IFN receptor system may be induced by cell differentiation and activation in a broader spectrum of cells.…”

“…Others have reported that human blood monocytes gain responsiveness to IFNduring differentiation to DCs, and that these DCs induce proliferation of regulatory T cells (29) and modulation of the Th1/Th2 response (49). In a different study it was shown that intrahepatic CD3 Ϫ DX5 ϩ NK cells express the IFN-receptor chains and contribute to the antitumor activities of IFN- (28). Therefore, as with type I IFN, type III IFNs possess immunomodulatory activities, which suggests that the IFN-s can stimulate the antiviral host response through different mechanisms, and also that this class of cytokines has functions beyond antiviral defense, as already suggested (26 -28).…”

“…Although this also involves induction of tumor apoptosis (28), it seems primarily to be mediated by host immune cells, with NK cells being ascribed particularly important roles (27,28). Moreover, IFN-seems to have immunomodulatory functions, because IFN--stimulated human monocyte-derived dendritic cells (DCs) induce proliferation of FOXP3-expressing suppressor T cells with contact-dependent suppressive activity on T cell proliferation (29).…”

Structure and function of interleukin-22 and other members of the interleukin-10 family

“…At the biological level, IFN-k1, IFN-k2, and IFN-k3 cytokines are more related to type I IFN, sharing the establishment of antiviral protection [97], antiproliferative [96], and antitumor [98][99][100] activities (reviewed in [101]). These cytokines activate the same JAK-STAT pathway, leading to the activation of STAT1/STAT2/IRF9 transcription factor complexes [4,5,96].…”

Type III interferon induces apoptosis in human lung cancer cells

“…More than 300 genes regulated by IFNs are implicated in apoptosis (15)(16)(17)(18). Previous studies have demonstrated the antitumor potential of type III IFNs in mouse melanoma (19) and fibrosarcoma (20,21), human colorectal adenocarcinoma (22), glioblastoma (23), pancreatic neuroendocrine tumor (24) and colorectal carcinoma (25). There is also a report indicating that IFNλ induces apoptosis in non-small cell lung cancer (NSCLC) cells (26).…”