Abstract

Simple SummaryThe crucial immune stimulatory functions exerted by Type I Interferons (IFNs) in cancer settings have been not only widely demonstrated during the last fifty years but also recently harnessed for therapy. However, depending on the dose and timing, and the downstream induced signatures, Type I IFNs can and do foster cancer progression and immune evasion. Dysregulations of Type I IFN signaling cascade are more and more frequently found in the tumor microenvironment, representing critical determinants of therapeutic innate and adaptive resistance to several anticancer treatments. Understanding when and through which genetic signatures Type I IFNs control or promote cancer growth is extremely urgent in order to prevent and by-pass the deleterious clinical effects and develop optimized innovative (combinatorial) strategies for an effective cancer management.Type I Interferons (IFNs) are key regulators of natural and therapy-induced host defense against viral infection and cancer. Several years of remarkable progress in the field of oncoimmunology have revealed the dual nature of these cytokines. Hence, Type I IFNs may trigger anti-tumoral responses, while leading immune dysfunction and disease progression. This dichotomy relies on the duration and intensity of the transduced signaling, the nature of the unleashed IFN stimulated genes, and the subset of responding cells. Here, we discuss the role of Type I IFNs in the evolving relationship between the host immune system and cancer, as we offer a view of the therapeutic strategies that exploit and require an intact Type I IFN signaling, and the role of these cytokines in inducing adaptive resistance. A deep understanding of the complex, yet highly regulated, network of Type I IFN triggered molecular pathways will help find a timely and immune“logical” way to exploit these cytokines for anticancer therapy.

Highlights

  • In the 1990s, the “danger theory” proposed by Polly Matzinger and colleagues upset the traditional view of immunity as response to solely alien microbes and molecules [1].it seemed clear that immune responses can be triggered by alarm signals released by the body’s own cells following changes in tissue and organ homeostasis or integrity, as it happens during cancer and viral infection

  • Antiviral and antitumor immunity share common cell-autonomous responses driven by the emission of danger signals, best known as damage-associated molecular patterns (DAMPs), which actively contribute to the establishment of a productive and long-lasting immune response allowing to clear cancer cells and viral invaders [2]

  • These transcriptional factors translocate to the nucleus, where IRF3, NF-κB, and activated protein 1 (AP1) trigger a first wave of IFN-β production [57,58,59], commonly observed within 1–4 h after stimulation, while IRF7 regulates a positive feedback loop leading to a secondary burst of IFN-α secretion [60]

Read more

Summary

Introduction

In the 1990s, the “danger theory” proposed by Polly Matzinger and colleagues upset the traditional view of immunity as response to solely alien microbes and molecules [1]. Type III IFNs are the latest class to be described and include up to four members in humans: IFN-λ1, IFN-λ2, and IFN-λ3, known as interleukin (IL)-29, IL28-A, and IL-28B, respectively, and IFN-λ4 [13]. Their peculiarity is to be structurally similar to IFN-γ but functionally identical to IFN-α/β. Type III IFNs essentially exert their biological activities on epithelial and immune cells by engaging a receptor complex composed of the IFNLR1 ( known as IL-28AR) and the IL-10R2 chains [14]. Type I IFNs in oncology and emphasizing the ability of these cytokines to induce cancer adaptive resistance and immune evasion

Type I IFNs: A Complex Signaling Network
Upstream Triggers of Type I IFNs
Downstream Effectors of Type I IFNs
Type I IFN-Induced Genetic and Epigenetic Signatures
Type I IFNs and Cancer: A Troubled Relationship
Type I IFNs and Cancer Immunosurveillance
Type I IFNs and Cancer Immunoescape
Type I IFNs and Cancer Therapy
Type I IFNs and Cytotoxic Therapies
Type I IFN Monotherapies
Type I IFNs and Immunotherapies
Type I IFNs and Therapy Resistance
Findings
Conclusions and Future Perspectives

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call

Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.