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.

FIG. 1.

Ligand-inducible elimination. (A) Eliminative signaling during the robust response to the low doses of Type I interferon (IFN1) leading to a limited receptor site occupancy (in this example, 20%). A resulting signaling induces the expression of robust interferon (IFN)-stimulated genes [mostly participating in establishing of an antiviral state but not in antiproliferative effects (Levin and others 2011)], and downregulation of engaged receptors (20% of total binding sites). As a result of this downregulation, the subsequent exposure of this cell to the next pulse of IFN1 (at similar dose) will decrease the chances of promptly firing another signaling cascade only by 20%. Yet, the responses to a greater dose of the ligands might be attenuated to a greater extent. (B) Eliminative signaling during the tunable response to the high doses of the ligand that will occupy a substantial share of receptors (in this example, 80%). A resulting signaling induces the expression of tunable IFN-stimulated genes (ISGs) [that are essential for mounting an efficient antiproliferative response (Levin and others 2011)], and downregulation of engaged receptors (80% of total binding sites). As a result, this cell is rendered nearly insensitive to the subsequent exposure to IFN. Color images available online at www.liebertpub.com/jir

FIG. 2.

Eliminative signaling by IFN1. The concept of eliminative signaling (Huangfu and Fuchs 2010) is illustrated specifically on the example of IFN1 responses. IFN1 binds to the receptor (IFNAR) to activate JAK (stem signaling). JAK serves as a central signaling dispatcher that further distributes the cascades between forward signaling (ie, activation of STAT resulting in the transcriptional activation of ISGs) and eliminative signaling [ie, activation of protein kinase D2 (PKD2) and subsequent downregulation of the receptor]. Unrelated ligands such as vascular endothelial growth factor (VEGF) or tumor necrosis factor-α (TNF-α) could utilize PKD2 or basal pathway to eliminate the receptor without benefits of forward signaling and ISG induction.

FIG. 3.

Ligand-independent elimination. Both ligand-inducible (upper scenario, similar to Fig. 1A) and ligand-independent (lower scenario) are depicted. While the former attenuates the IFN1 pathway, the latter abrogates IFN1 responses. The sensitivity of a cell to IFN1 will varies depending on the sequence of eliminative stimuli that it would be exposed to. If this cell first encounters IFN1, elimination of receptor will be secondary to the activation of IFN1-elicited transcriptional program and ensuing antitumorigenic activities. These activities will not be evoked (although receptor will be lost) if the cell encounters a cross-eliminative signal (eg, VEGF) before being exposed to IFN1. Color images available online at www.liebertpub.com/jir

FIG. 4.

Sources and targets of eliminative signaling. Examples of stimuli that activate inside-out or/and outside-in modes of eliminative signaling leading to acceleration of IFNAR1 degradation and desensitization of cells to antitumorigenic effects of IFN1 are depicted. These stimuli include intracellular (for example, integrative stress response, ISR) and extracellular (eg, danger-associated molecular patterns, DAMPs) triggers. As a result of these eliminative pathways, levels of IFN1 receptor and sensitivity to IFN1 will be decreased in cells that contribute to the tumor formation, including cancer cells themselves as well as benign cells of stromal, angiogenic, and immune compartments leading to an overall effect of attenuating direct and indirect antitumorigenic effects of endogenous or pharmacologic IFN1. Color images available online at www.liebertpub.com/jir