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A key component of mammalian immunity against viruses and cancer is a family of cytokines called the interferons (IFNs, so called because they ‘interfere’ with virus replication). The IFNs are classified into two groups, type I and type II. Type I (α/β) IFNs are produced by most cell types in response to viral infection, whereas type II IFN (called IFN-γ) is made by a select subset of immune system cells and is not virus inducible.

Type I IFNs (e.g.IFN-α2) were approved by the Food & Drug Administration (FDA) in 1986 as the first commercial anticancer biotherapeutic, and are currently employed in the treatment of over twenty human cancers. It is thought that the IFNs exert their antitumor effects by modulation and reactivation of the immune response to the tumor and/or by direct tumoricidal activity, but the underlying mechanisms remain poorly described. In the years preceding their approval by the FDA, the IFNs were touted as a potential ‘silver bullet’ cure for many forms of cancer, even making the cover of Time magazine in 1980. Unfortunately, these cytokines have, in recent years, fallen out of favor with many oncologists because of their very unpleasant side-effects. Nevertheless, IFNs continue to be used in the clinic and provide spectacular cures of several highly malignant cancers (such as AIDS-associated lymphomas and metastatic renal cell carcinoma), highlighting their Janus-faced nature.

The primary problem with IFN therapy is that IFN is, of course, also a potent antiviral cytokine and triggers a powerful innate immune response in the patient, whose body responds to systemic therapeutic IFN as it would to an acute viremia. Efforts are currently underway to target IFN delivery to the tumor site (particularly for solid tumors), but an equally compelling avenue of research is to determine the mechanism(s) by which IFNs selectively mediate their cytotoxic effects, and exploit these mechanisms to make IFN a more potent therapeutic (and thereby reduce its effective dose by, hopefully, at least one order of magnitude). Our laboratory is therefore very interested in the molecular processes by which IFNs specifically exert their anti-proliferative effects. We have recently identified novel pathways by which the IFNs induce cell survival and death and are currently elucidating these mechanisms.

Another area of research in the laboratory is to understand how type I IFNs and other antiviral genes are induced after virus infection. In a current model, virus replication in the cytosol activates at least three classes of transcription factors to induce primary antiviral genes (including type I IFNs). Of these factors, we are particularly interested in NF-κB, and are currently defining its mechanism of activation and role in antiviral responses.

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