Hope and Fear for Interferon: The Receptor-Centric Outlook on the Future of Interferon Therapy

Abstract

After several decades of intense clinical research, the great promise of Type I interferons (IFN1) as the anticancer wonder drugs that could cure or, at the very least, curb the progression of various oncological diseases has regrettably failed to deliver. Severe side effects and low efficacy of IFN1-based pharmaceutics greatly limited use of these drugs and further reduced the enthusiasm of clinical oncologists for future optimization of IFN1-based therapeutic modalities. Incredibly, extensive clinical studies to assess the efficacy of IFN1 alone or in combination with other anticancer drugs have not been paralleled by an equal scope in defining the determinants that confer cell sensitivity or refractoriness to IFN1. Given that all effects of IFN1 on malignant and benign cells alike are mediated by its receptor, the mechanisms regulating these receptor cell surface levels should play a paramount role in shaping the magnitude and duration of IFN1-elicited effects. These mechanisms and their role in controlling IFN1 responses, as well as an ability of a growing tumor to commandeer these events, are the focus of our review. We postulate that activation of numerous signaling pathways leading to elimination of IFN1 receptor occurs in cancer cells and benign cells that contribute to tumor tissue. We further hypothesize that activation of these eliminative pathways enables the escape from IFN1-driven suppression of tumorigenesis and elicits the primary refractoriness of tumor to the pharmaceutical IFN1.

Type I Interferon Controls Propagation of Long Interspersed Element-1

“…These cytokines act by interacting with the Type 1 IFN receptor that consists of IFNAR1 and IFNAR2 chains and mediates all cellular effects of IFN (2)(3)(4). Association of IFN with a heteromeric receptor leads to activation of Janus kinases TYK2 and JAK1 and phosphorylation-dependent activation of the Signal Transducers and Activators of Transcription (STAT1/2) proteins.…”

“…Association of IFN with a heteromeric receptor leads to activation of Janus kinases TYK2 and JAK1 and phosphorylation-dependent activation of the Signal Transducers and Activators of Transcription (STAT1/2) proteins. These proteins interact with IRF9 to form a potent transcription factor that up-regulates the expression of several hundreds of IFNstimulated genes, whose products both elicit anti-viral effects and contribute to the development of the inflammatory tissue injury (2,3,(5)(6)(7)(8). Since integration of viruses into host DNA induces genetic changes (9), it may be hypothesized that antiviral cytokines including IFN can also play a role in maintaining the integrity of the host genome.…”

Critical Roles for Rictor/Sin1 Complexes in Interferon-dependent Gene Transcription and Generation of Antiproliferative Responses

“…Despite the fact that new effective targeted therapies have replaced IFNs in the management of certain diseases, these cytokines still play key roles in the treatment of certain malignancies, such as myeloproliferative neoplasms (8,9). Notably, there has recently been renewed enthusiasm for the clinical use of IFNs in malignancies, taking advantage of the emerging better understanding of their biological functions and the pathophysiological mechanisms in which IFNs are involved (7,10).…”

Hemagglutinin of Influenza A Virus Antagonizes Type I Interferon (IFN) Responses by Inducing Degradation of Type I IFN Receptor 1

“…The level of IFNAR1 was shown to be important for stimulating the JAK/STAT-mediated downstream signaling pathway (20). However, high levels of type I IFN decrease the level of IFNAR1, presumably as a negative regulatory mechanism.…”