Interferon lambda: a new sword in cancer immunotherapy

Abstract

The discovery of the interferon-lambda (IFN-λ) family has considerably contributed to our understanding of the role of interferon not only in viral infections but also in cancer. IFN-λ proteins belong to the new type III IFN group. Type III IFN is structurally similar to type II IFN (IFN-γ) but functionally identical to type I IFN (IFN-α/β). However, in contrast to type I or type II IFNs, the response to type III IFN is highly cell-type specific. Only epithelial-like cells and to a lesser extent some immune cells respond to IFN-λ. This particular pattern of response is controlled by the differential expression of the IFN-λ receptor, which, in contrast to IFN-α, should result in limited side effects in patients. Recently, we and other groups have shown in several animal models a potent antitumor role of IFN-λ that will open a new challenging era for the current IFN therapy.

Figure 1

IFN-α and IFN-λ receptor systems and cell signaling. IFN-α and IFN-λ interact with distinct receptors, but the downstream signaling is similar. IFN-α interacts with receptors composed of IFNAR1 and IFNAR2, and IFN-λ interacts with a receptor composed of a specific chain, IFN-λR1, and IL-10R2, a shared subunit with IL-10, IL-22, and IL-26. Both IFNs lead to the activation of the Jak kinases (Jak1 and Tyk2) and the formation of the transcription-complex-designated IFN-stimulated gene factor 3 (ISGF3), which includes p48, Stat1, and Stat2. ISGF3 complex binds to the IFN-stimulated response element (ISRE) and induces gene transcription.

Figure 2

Cellular targets for type I and type III IFNs. Response to IFN-α and IFN-λ in cells from different origins in human. The IFN response was assessed by measuring the IFN-induced cell signaling (Stat activation) and cell activity (MHC class I antigen stimulation). In contrast to IFN-α, only restricted cells respond to IFN-λ, including epithelial-like cells, forming the major organs of the body.