More than half a century has passed since interferons (IFNs) were first discovered. Since then, they have evolved from a “cure-all” for cancer, as they were initially touted, to a more tempered yet equally vital role in treating a number of different disease states, including many different types of cancer.
Although they have been replaced by more targeted molecular therapies in some instances, IFNs still have an important role to play in cancer therapeutics. This potential is becoming increasingly evident as researchers gain a better understanding of the biology of IFNs and uncover new isoforms and genetic variants, including the discovery last year of a new class of IFNs (type III).
What Are Interferons?
IFNs were first characterized in 1957 and were named for their role in a process called viral interference, in which one virus interferes with the growth of another, unrelated virus. By the mid-1970s, IFN research began to take off and, following reports of antitumor activity in mice, they began to be used in the treatment of a wide range of different cancers.
IFNs are part of the cytokine family of proteinsâŽ¯small, hormone-like proteins that play an important role in communication between cells and their external environment, produced in response to external stimuli. They are classified into three groups according to which receptor they bind:
Type I IFNs, which all use the type I IFN receptor, include IFNα, β, δ, ε, κ, and ω
Type II IFNs, which use the type II IFN receptor, consist of IFNγ
Type III IFNs, which use an IFNλ-specific receptor, consist of IFNλ
The groups differ not just in which receptor they bind, but also in the cells that produce them and in their genetic variation. While IFNγ is encoded by a single gene, IFNλ has four subtypes, and IFNα has up to 14. The type I IFNs are the most broadly expressed and can be produced by virtually any cell in the body, though IFNα is produced primarily by macrophages and dendritic cells, while IFNβ is expressed predominantly by fibroblasts. The type II and type III IFNs are much more restricted in the types of cells that both produce and respond to them.
IFNs exert their cellular effects by binding to their specific receptor on the membrane of a target cell and initiating intracellular signaling events. This is another important point of divergence between the three groups. The type I and type III IFNs have significant overlap in the downstream signaling events that they initiate. They activate the tyrosine kinases Janus kinase 1 (JAK1) and tyrosine kinase 2 (TYK2), resulting in the formation of heterodimers of signal transducer and activator of transcription 1 and 2 (STAT1/2), which subsequently migrate into the nucleus and associate with the transcription factor IFN regulatory factor 9 (IRF9) to form the IFN-stimulated gene factor 3 (ISGF3) complex. This complex in turn activates the transcription of IFN target genes. On the other hand, the type II IFN, IFNγ, signals via JAK1 and JAK2 and activates different downstream signaling events.
A Glimpse at IFN Pathways
IFN indicates interferon; IRF, interferon regulatory factor; ISG, interferonstimulated gene; JAK, Janus kinase; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; TYK, tyrosine kinase; STAT, signal transducer and activator of transcription.
Adapted from Katsoulidis E, Kaur S, Platanias LC. Deregulation of interferon signaling in malignant cells. Pharmaceuticals. 2010;3:406-418.
Interferons as Anticancer Therapy
IFNs clearly act upstream of many important signaling pathways, and researchers have elucidated a plethora of different cellular roles besides their namesake activity of viral interference. For example, they play vital roles in regulating both the innate and adaptive immune responses, and in the activation, migration, differentiation, and survival of various different types of immune cell. In the 1990s, the role of IFNs began to be further delineated, and there was much excitement as it became apparent that they had so-called non-antiviral effectsâŽ¯a variety of effects on cell growth, apoptosis, and angiogenesis (new blood vessel formation) were observed, and this is when clinicians began to realize the potential anticancer applications of IFNs.
Over the decades that followed the discovery of the cytotoxic effects of IFNs, they were touted as a potential “magic bullet” treatment for cancer. While they ultimately did not offer the cure-all that many had hoped, they did become the first treatment for numerous types of hematological cancers and solid tumors, and offered significant hope to patients. At one time or another, they were used clinically and were standard-of-care treatment for chronic myeloid leukemia (CML), hairy cell leukemia (HCL), T- and B-cell lymphomas, melanomas, renal cell carcinomas, and AIDS-associated Kaposi sarcoma.