Review
Interferon signaling in cancer. Non-canonical pathways and control of intracellular immune checkpoints

https://doi.org/10.1016/j.smim.2019.101299Get rights and content

Highlights

  • IFNs activate many signaling pathways in cancer cells.

  • Non-canonical, non-STAT, pathways are critical for the IFN-antitumor response.

  • IFN-engaged mTORC1 and/or mTORC2 pathways control ISG mRNA translation and/or transcription.

  • SLFNs control IFN-induced STAT responses in some malignant cells and may act as intracellular immune checkpoints.

Abstract

The interferons (IFNs) are cytokines with important antineoplastic and immune modulatory effects. These cytokines have been conserved through evolution as important elements of the immune surveillance against cancer. Despite this, defining their precise and specific roles in the generation of antitumor responses remains challenging. Emerging evidence suggests the existence of previously unknown roles for IFNs in the control of the immune response against cancer that may redefine our understanding on how these cytokines function. Beyond the engagement of classical JAK-STAT signaling pathways that promote transcription and expression of gene products, the IFNs engage multiple other signaling cascades to generate products that mediate biological responses and outcomes. There is recent emerging evidence indicating that IFNs control the expression of both traditional immune checkpoints like the PD-L1/PD1 axis, but also less well understood “intracellular” immune checkpoints whose targeting may define new approaches for the treatment of malignancies.

Introduction

The interferons (IFNs) were originally described as soluble factors with antiviral properties [[1], [2], [3]]. Years later it was understood that the biological functions of these cytokines extend well beyond their antiviral activities and that they have important immune-modulatory and antineoplastic effects [[4], [5], [6], [7], [8], [9]]. It is now well established that IFNs are key elements of the immune surveillance against cancer and have important antineoplastic activities when administered to patients suffering from various types of cancers by exerting both direct effects on the malignant cells, as well as indirect effects on cells of the immune system [10].

There are three known types of IFNs: I, II and III. Type I (IFNα/β) and type III (IFNλ) IFNs are produced by many different types of mammalian cells, whereas the only type II IFN, IFNγ, is produced mainly by T cells and natural killer (NK) cells [[11], [12], [13]]. Once secreted, the different IFNs bind to specific cell surface receptors to initiate biochemical signals that mediate their biological effects. The different IFN receptors have each two binding subunits and include the Type I (IFNα/β) receptor (IFNAR1 and IFNAR2), the Type II (IFNγ) receptor (IFNGR1 and IFNGR2), and the Type III (IFNλ) receptor (IFNLR1 and IL10R), respectively [[11], [12], [13]]. The binding of the different IFNs to their corresponding receptors triggers activation of multiple intracellular signaling cascades that ultimately drive the expression of IFN-stimulated genes (ISGs) that control cell cycle progression, proliferation, apoptosis, differentiation, migration, and survival [[12], [13], [14]].

After the realization that IFNs have important antitumor activities in the late 70’s and early 80’s, there was high hope and expectation that the use of these cytokines as therapeutic agents was going to dramatically transform cancer treatment for many types of tumors and cure many patients [[15], [16], [17], [18]]. With time it became clear that IFN-treatment will not meet this very high expectation. Nevertheless, over the years IFNs have had a major impact in the treatment of several malignancies and they improved the survival of hundreds of thousands of patients with specific types of cancer, including different hematologic malignancies, melanoma, renal cell carcinoma, and Kaposi's sarcoma [14,19]. However, a complicating factor of IFN-treatment has been the substantial toxicity of these cytokines when used at high doses, and this has been a limiting factor in a number of cases [14,19].

The early clinical studies using IFNs underscored the need for a better understanding of the mechanisms by which these cytokines mediate direct antitumor effects and elicit immune responses. This is particularly important in the current medical era, with emerging new immune therapeutic approaches resulting in improved outcomes for patients with previously fatal malignancies [20]. Surprisingly, activation of IFN-signaling pathways and downstream expression of ISGs has been shown to correlate with either response or resistance to immune therapies [[21], [22], [23]]. The complex mechanisms by which IFNs impact anti-tumor immune responses are still far from being completely understood. Dissecting and defining these mechanisms may allow the development of novel immune therapeutic approaches that circumvent pro-tumorigenic IFN-activated resistance mechanisms, while at the same time promoting IFN-dependent antitumor immunity. New insights on the direct and indirect antitumor effects of IFNs resulting from research in the last few years have uncovered new treatment opportunities and potential therapeutic combinations that are currently being exploited or may be investigated in the future [24].

Section snippets

Overview of non-canonical signaling pathways in the regulation of ISG expression

The Type I and II IFN receptors are expressed widely in mammalian cells [13,14,[25], [26], [27], [28], [29]], while the Type III IFN receptor appears to show more tissue selectivity towards epithelial cells [3,30]. Engagement of all three types of IFN receptors (IFNRs) results in activation of JAK/STAT signaling pathways [13,[26], [27], [28], [29], [30], [31], [32]]. The engagement of JAK/STAT cascades appears to be a “universal” or so called “classical” [27,28] or “canonical” [31] pathway,

Antitumor Immune responses and non-canonical versus canonical IFN-pathways

The possibility that IFNs promote host’s anti-tumor responses was first raised from studies in which IFNα treatment increased survival [118] and inhibited the growth and formation of lung metastases [119] in mice inoculated with IFN-resistant cancer cells. Moreover, injection of immunocompetent mice with a neutralizing antibody to IFNα/β, which did not affect the growth of malignant cells in vitro, increased tumor growth and decreased survival of the mice, indicating that endogenous Type I IFNs

Conclusions and future directions

There has been a lot of progress in recent years in understanding the mechanisms by which IFNs mediate biological responses. The need to fully understand these mechanisms appears to be more urgent and impactful than ever because of the rapid advances in the cancer immunotherapy field and the central role that IFNs play in the control of immune checkpoint regulation in cells of the immune system. The better understanding of IFN-signaling mechanisms, especially as it relates to the roles of

Declaration of Competing Interest

Declarations of interest: none.

Acknowledgments

Dr. Platanias’s research is supported by the National Institutes of Health grants R01-CA121192 and R01-CA77816, and grant I01-CX000916 from the Department of Veterans Affairs. This article is dedicated to the memory of Barbara Kroczynska who over the years made significant contributions to the IFN-signaling field.

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