Type I Interferons as Joint Regulators of Tumor Growth and Obesity.

Sandra Gessani,Filippo Belardelli

doi:10.3390/cancers13020196

Sandra Gessani, Filippo Belardelli

Open Access

https://doi.org/10.3390/cancers13020196

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Abstract

Simple SummaryThe escalating global epidemic of overweight and obesity is a major public health and economic problem, as excess body weight represents a significant risk factor for several chronic diseases including cancer. Despite the strong scientific evidence for a link between obesity and cancer, the mechanisms involved in this interplay have not yet been fully understood. The aim of this review is to evaluate the role of type I interferons, a family of antiviral cytokines with key roles in the regulation of both obesity and cancer, highlighting how the dysregulation of the interferon system can differently affect these pathological conditions.Type I interferons (IFN-I) are antiviral cytokines endowed with multiple biological actions, including antitumor activity. Studies in mouse models and cancer patients support the concept that endogenous IFN-I play important roles in the control of tumor development and growth as well as in response to several chemotherapy/radiotherapy treatments. While IFN-I signatures in the tumor microenvironment are often considered as biomarkers for a good prognostic response to antitumor therapies, prolonged IFN-I signaling can lead to immune dysfunction, thereby promoting pathogen or tumor persistence, thus revealing the “Janus face” of these cytokines in cancer control, likely depending on timing, tissue microenvironment and cumulative levels of IFN-I signals. Likewise, IFN-I exhibit different and even opposite effects on obesity, a pathologic condition linked to cancer development and growth. As an example, evidence obtained in mouse models shows that localized expression of IFN-I in the adipose tissue results in inhibition of diet–induced obesity, while hyper-production of these cytokines by specialized cells such as plasmacytoid dendritic cells in the same tissue, can induce systemic inflammatory responses leading to obesity. Further studies in mouse models and humans should reveal the mechanisms by which IFN-I can regulate both tumor growth and obesity and to understand the role of factors such as genetic background, diet and microbioma in shaping the production and action of these cytokines under physiological and pathological conditions.

Highlights

Interferon (IFN) was first identified more than 60 years ago as a factor released by virus-infected cells capable of inhibiting viral replication in target cells
Along with pathogen-associated molecular patterns (PAMP) and damage-associated molecular pathways (DAMP), IFN-I can be produced in response to rare physiologic stimuli such as colony stimulating factor (CSF)1, receptor activator of NF-kB ligand (RANK) and estrogens [10]
These balanced responses are finetuned by host factors at multiple levels and loss of this fine-tuning can result in sustained IFN signaling, immunosuppression and tissue damage, which has been implicated in pathogenesis of chronic viral infections, autoimmune diseases and cancer [18]

Summary

Introduction

Interferon (IFN) was first identified more than 60 years ago as a factor released by virus-infected cells capable of inhibiting viral replication in target cells. IFN-I induce balanced responses in which activating signals that induce antiviral states and promote immune responses are counterbalanced by suppressive signals that limit toxicity to the host These balanced responses are finetuned by host factors at multiple levels and loss of this fine-tuning can result in sustained IFN signaling, immunosuppression and tissue damage, which has been implicated in pathogenesis of chronic viral infections, autoimmune diseases and cancer [18]. Overweight and obesity are significant risk factors for a number of chronic disorders, including cardiovascular diseases and type 2 diabetes mellitus (T2D) and, more importantly, several cancer types This condition affects all stages of cancer development and may have a negative impact on the response to therapy. We will discuss the role of endogenous IFN-I in the control of both tumor growth and obesity highlighting how the dysregulation of the IFN-I system may result in different and even opposite effects in these pathological conditions

Type I Interferons and Cancer

The Link between Obesity and Cancer

The Interplay between Type I Interferon and Obesity

Focusing on One Specific Cancer Model

Perspectives and Future Directions

Conclusions