The role of interferons in the treatment of malignant neoplasms

Interferons (IFNs) are proteins with a wide range of biological effects. IFNs have antiviral and antiproliferative properties. They modulate both the immune system and the expression of cell phenotype. In the past decade, the IFNs have received intense clinical scrutiny. Alpha IFN is the best studied and displays activity in many neoplastic diseases; it has shown the most promise in the hematological cancers although several solid tumors, including epidemic Kaposi's sarcoma, renal cell carcinoma, and melanoma, respond. No neoplastic disease, however, has been cured by the IFNs. IFN seems to be most active in the setting of minimal residual disease, and clinical studies evaluating its role in the adjuvant setting are under way. Other areas of research include trials combining IFN with cytotoxic drugs or other biological response modifiers, and maintenance IFN to prolong remissions following successful induction therapy.     

Present role and future potential of type I interferons in adjuvant therapy of high-risk operable melanoma

Few molecular therapeutic approaches have been so rigorously investigated in relation to the pathophysiology and outcome of human diseases as type I interferons. Historically, IFNs were discovered after the phenomenon of ‘interference’ was first described by Isaacs and Lindenmann in 1957, and for years IFNs (IFN) were considered as potential “antiviral penicillins” until the broader spectrum of effects upon normal cell physiology, the natural and adaptive immune systems, and tumor growth and proliferation were described. Interferon beta (IFNβ) was the second human gene after insulin to be cloned, and it codes for the first cytokine used to treat human malignancies. Despite the progress in understanding and treating cancer over the last 25 years, IFN alpha (IFN) remains the most commonly used biologically active cytokine in the treatment of solid tumors, and for some like melanoma, the only successful agent. In this review we discuss the role of type I interferons in the pathophysiology and treatment of melanoma, with emphasis on the 22 years of work conducted at the University of Pittsburgh. We discuss potential mechanisms that partially explain the clinical benefit, and set the groundwork for building upon, the design of more effective treatments for this disease.     

Immunological functions of macrophages and their regulation by interferons

Important progress has been recently made on the identification, physico-chemical properties, purification and production by recombinant technology of a series of immunoregulatory mediators, including interferons (IFNs). It is now possible to appreciate which part play IFNs in the regulation and activation of monocyte-macrophage (MO) functions. The present review discusses old concepts, such as Macrophage-Activating Factor (MAF) activity, at the light of recent data on the effects of IFN alpha, beta and gamma on four main immunological properties of MO, namely intracellular killing of microorganisms, non specific lysis of tumor cells, antigen presentation and secretion of soluble immunoregulatories molecules such as interleukin 1. All three IFN species enhance such functions, whereas enhancement of membrane class II major histocompatibility complex antigens is a unique property of IFN gamma. The role of IFNs, especially IFN gamma, as major MAF in vitro and in vivo is discussed.     

Retinoic acid or methionine enhance interferon's inhibition of the transformed phenotype with no effect on tumorigenicity

Retinoic acid (RA) and methionine were studied for their relative effectiveness in enhancing the ability of interferons (IFNs) to reverse the phenotype of murine methylcholanthrene (MCA)-transformed cells and human osteosarcoma (OHA) cells. Treatment with RA (1 microM) and methionine (25mM) alone had minimal or no effect on the proliferation of MCA and OHA cells or on the ability to form tumors in animals. Combination of these two agents with IFNs however, potentiated the inhibitory effects of IFNs on proliferation and colony formation of MCA transformed cells but not on their tumorigenicity. Similarly in human tumor OHA cells, only the combination of IFN and RA was more effective than IFN alone on proliferation and colony formation but not on tumorigenicity. Thus, the enhanced effects of combined treatments on cell proliferation in vitro could be distinguished from the inhibitory effects of IFNs on tumorigenicity in both murine transformed cells and human tumor cells.     

Free radicals as possible mediators of the actions of interferon

Interferons (IFNs), in addition to their antiviral action, have been shown to inhibit cell proliferation, induce differentiation of some tumor cells, activate NK cells and macrophages, and modulate phagocytosis. The exact mechanism(s) by which IFN can bring about these pleiotropic actions is not known. Recent studies, including our own (presented here), showed that IFN can augment free radical generation in the cells. Free radicals can stimulate lymphocytes mitogenically and activate macrophages and NK cells. It is also known that activated machophages and polymorphs produce oxidative metabolites, such as hydrogen peroxide, which is responsible for sterilizing action against microorganisms and cytotoxic activity against tumor cells. Free radicals are also known to inhibit cell division. Since IFN can augment free radical generation, it is suggested that free radicals mediate some of the actions of IFN.     

The GRIMs: a new interface between cell death regulation and interferon/retinoid induced growth suppression

Cytokines and vitamins play a central role in controlling neoplastic cell growth. The interferon (IFN) family of cytokines regulates antiviral, anti-tumor, antimicrobial, differentiation, and immune responses in mammals. Significant advances have been made with respect to IFN-induced signal transduction pathways and antiviral responses. However, the IFN-induced anti-tumor actions are poorly defined. Although IFNs themselves inhibit tumor growth, combination of IFNs with retinoids (a class of Vitamin A related compounds) strongly potentiates the IFN-regulated anti-tumor action in a number of cell types. To define the molecular mechanisms involved in IFN/retinoid (RA)-induced apoptosis we have employed a genetic approach and identified several critical genes. In this review, I provide the current picture of IFN- RA- and IFN/RA-regulated growth suppressive pathways. In particular, I focus on a novel set of genes, the genes-associated with retinoid-interferon induced mortality (GRIM). GRIMs may be novel types of tumor suppressors, useful as biological response markers and potentially novel targets for drug development.     

Interferons: Success in anti-viral immunotherapy

The interferons (IFNs) are glycoproteins with strong antiviral activities that represent one of the first lines of host defense against invading pathogens. These proteins are classified into three groups, Type I, II and III IFNs, based on the structure of their receptors on the cell surface. Due to their ability to modulate immune responses, they have become attractive therapeutic options to control chronic virus infections. In combination with other drugs, Type I IFNs are considered as “standard of care” in suppressing Hepatitis C (HCV) and Hepatitis B (HBV) infections, while Type III IFN has generated encouraging results as a treatment for HCV infection in phase III clinical trials. However, though effective, using IFNs as a treatment is not without the need for caution. IFNs are such powerful cytokines that affect a wide array of cell types; as a result, patients usually experience unpleasant symptoms, with a percentage of patients suffering system wide effects. Thus, constant monitoring is required for patients treated with IFN in order to reach the treatment goals of suppressing virus infection and maintaining quality of life.     

Type I interferon response in the central nervous system

This review is dedicated to the influence of type I IFNs (also called IFN-alpha/beta) in the central nervous system (CNS). Studies in mice with type I IFN receptor or IFN-beta gene deficiency have highlighted the importance of the type I IFN system against CNS viral infections and non-viral autoimmune disorders. Direct antiviral effects of type I IFNs appear to be crucial in limiting early spread of a number of viruses in CNS tissues. Type I IFNs have also proved to be beneficial in autoimmune disorders like multiple sclerosis or experimental autoimmune encephalitis, probably through immunomodulatory effects. Increasing efforts are done to characterize IFN expression and response in the CNS: to identify type I IFN producing cells, to decipher pathways leading to type I IFN expression in those cells, and to identify responding cells. However, reversible and irreversible damages consecutive to chronic exposure of the CNS to type I IFNs underline the importance of a tightly regulated type I IFN homeostasis in this organ.     

IFNB1/interferon-β-induced autophagy in MCF-7 breast cancer cells counteracts its proapoptotic function

IFNB1/interferon (IFN)-β belongs to the type I IFNs and exerts potent antiproliferative, proapoptotic, antiangiogenic and immunemodulatory functions. Despite the beneficial effects of IFNB1 in experimental breast cancers, clinical translation has been disappointing, possibly due to induction of survival pathways leading to treatment resistance. Defects in autophagy, a conserved cellular degradation pathway, are implicated in numerous cancer diseases. Autophagy is induced in response to cancer therapies and can contribute to treatment resistance. While the type II IFN, IFNG, which in many aspects differs significantly from type I IFNs, can induce autophagy, no such function for any type I IFN has been reported. We show here that IFNB1 induces autophagy in MCF-7, MDAMB231 and SKBR3 breast cancer cells by measuring the turnover of two autophagic markers, MAP1LC3B/LC3 and SQSTM1/p62. The induction of autophagy in MCF-7 cells occurred upstream of the negative regulator of autophagy MTORC1, and autophagosome formation was dependent on the known core autophagy molecule ATG7 and the IFNB1 signaling molecule STAT1. Using siRNA-mediated silencing of several core autophagy molecules and STAT1, we provide evidence that IFNB1 mediates its antiproliferative effects independent of autophagy, while the proapoptotic function of IFNB1 was strongly enhanced in the absence of autophagy. This suggests that autophagy induced by IFNB1 promoted survival, which might contribute to tumor resistance against IFNB1 treatment. It may therefore be clinically relevant to reconcile a role for IFNB1 in the treatment of breast cancer with concomitant inhibition of autophagy.     

Type I IFN protects against murine lupus

Both the type I (IFN-alpha beta) and type II (IFN-gamma) IFNs have been heavily implicated in the pathogenesis of systemic lupus erythematosus. To test the relative roles of these systems, congenic lupus-prone MRL/CD95(lpr/lpr) (MRL/lpr) mice lacking the type I IFN receptor (IFN-RI), type II IFN receptor (IFN-RII), or both, were derived. As expected, deficiency for IFN-RII protected MRL/lpr mice from the development of significant autoimmune-associated lymphadenopathy, autoantibodies, and renal disease. However, deficiency for the IFN-RI surprisingly worsened lymphoproliferation, autoantibody production, and end organ disease; animals doubly deficient for IFN-RI and IFN-RII developed an autoimmune phenotype intermediate between wild-type and IFN-RII-deficient animals, all correlating with an ability of type I IFN to suppress MRL B cell activation. Thus, type I IFNs protect against both the humoral and end organ autoimmune syndrome of MRL/lpr mice, independent of IFN-gamma. These findings warrant caution in the use of type I IFN antagonists in the treatment of autoimmune diseases and suggest further investigation into the interplay between the types I and II IFNs during the ontogeny of pathogenic autoantibodies.     

Interferons and cell growth control

Cytokines modulate cell growth, differentiation, and immune defenses in the vertebrates. Interferons (IFNs) are a unique class of cytokines that stimulate antiviral, antitumor and antigen presentation by inducing the expression of several cellular genes. Recent studies have identified a novel gene regulatory pathway activated by IFNs, which serves as a paradigm for most cytokine signal transduction pathways. A number of genes induced by IFNs participate in cell growth regulation and apoptosis. These include novel tumor suppressor genes. Although discovered as IFN-regulated factors, deletions of these genes cause leukemias in experimental models and in human patients. Genetic approaches have identified several novel regulators of apoptosis. Studies on the mechanism of action of these growth regulatory molecules are not only useful in identifying novel targets for the development of therapeutics but also help understand the molecular basis for loss of cell growth control and resistance to IFNs. This review focuses on the functions and roles of IFN regulated factors in cell growth control and mechanisms of disruption of IFN action in cancer cells.     

The roles of IFN gamma in protection against tumor development and cancer immunoediting

Interferon-gamma (IFN gamma) is a cytokine that plays physiologically important roles in promoting innate and adaptive immune responses. The absence of IFN gamma production or cellular responsiveness in humans and experimental animals significantly predisposes the host to microbial infection, a result that validates the physiologic importance of this cytokine in preventing infectious disease. Recently, an additional role for IFN gamma in preventing development of primary and transplanted tumors has been identified. Although there now appears to be a consensus that IFN gamma promotes host responses to tumors, the mechanisms by which this cytokine achieves its effects remain unclear. In this review, we briefly discuss key issues of the molecular cell biology of IFN gamma and its receptor that are most relevant to IFN gamma-dependent anti-tumor effects and then focus on the data implicating IFN gamma as a critical immune system component that regulates tumor development. Potential mechanisms underlying IFN gamma's anti-tumor effects are discussed and a preliminary integrative model of IFN gamma's actions on tumors is proposed. Finally, the capacity of IFN gamma and lymphocytes to not only provide protection against tumor development but also to sculpt the immunogenic phenotype of tumors that develop in an immunocompetent host is presented and introduced as a "cancer immunoediting" process.     

Role of type I interferons in the activation of autoreactive B cells

Type I interferons (IFNs) are a family of cytokines involved in the defense against viral infections that play a key role in the activation of both the innate and adaptive immune system. IFNs both directly and indirectly enhance the capacity of B lymphocytes to respond to viral challenge and produce cytotoxic and neutralizing antibodies. However, prolonged type I IFN exposure is not always beneficial to the host. If not regulated properly IFN can drive autoantibody production as well as other parameters of systemic autoimmune disease. Type I IFNs impact B-cell function through a variety of mechanisms, including effects on receptor engagement, Toll-like receptor expression, cell migration, antigen presentation, cytokine responsiveness, cytokine production, survival, differentiation and class-switch recombination. Type I IFNs are also cytotoxic for a variety of cell types and thereby contribute to the accumulation of cell debris that serves as a potential source for autoantigens. Type I IFN engagement of a variety of accessory cells further promotes B-cell survival and activation, as exemplified by the capacity of type I IFNs to increase the level of B-cell survival factors, such as B lymphocyte stimulator, produced by dendritic cells. Therefore, it is not surprising that the loss of expression of the type I IFN receptor can have dramatic effects on the production of autoantibodies and on the clinical features of systemic autoimmune diseases such as systemic lupus erythematosus.     

Interferon-alpha and cancer: mechanisms of action and new perspectives of clinical use

Interferons-alpha (IFN-alpha) are pleiotropic cytokines belonging to type I IFNs, extensively used in the treatment of patients with some types of cancer and viral disease. IFN-alpha can affect tumor cell functions by multiple mechanisms. In addition, these cytokines can promote the differentiation and activity of host immune cells. Early studies in mouse tumor models showed the importance of host immune mechanisms in the generation of a long-lasting antitumor response after treatment of the animals with IFN-alpha/beta. Subsequently, an ensemble of studies based on the use of genetically modified tumor cells expressing specific IFN molecules provided important information on the host-mediated antitumor mechanisms induced by the local production of IFN-alpha. Of note, several studies have then underscored new immunomodulatory effects of IFN-alpha, including activities on T cells and dendritic cells, which may lead to IFN-induced antitumor immunity. In addition, recent reports on new immune correlates in cancer patients responding to IFN-alpha represent additional evidence on the importance of the interactions of IFN-alpha with the immune system for the generation of a durable antitumor response. On the whole, this knowledge suggests the advantage of using these cytokines as adjuvants of cancer vaccines and for the in vitro generation of highly active dendritic cells to be utilized for therapeutic vaccination of cancer patients.     

Type III IFNs in pteropid bats: differential expression patterns provide evidence for distinct roles in antiviral immunity

Bats are known to harbor a number of emerging and re-emerging zoonotic viruses, many of which are highly pathogenic in other mammals but result in no clinical symptoms in bats. The ability of bats to coexist with viruses may be the result of rapid control of viral replication early in the immune response. IFNs provide the first line of defense against viral infection in vertebrates. Type III IFNs (IFN-λs) are a recently identified IFN family that share similar antiviral activities with type I IFNs. To our knowledge, we demonstrate the first functional analysis of type III IFNs from any species of bat, with the investigation of two IFN-λ genes from the pteropid bat, Pteropus alecto. Our results demonstrate that bat type III IFN has similar antiviral activity to type I and III IFNs from other mammals. In addition, the two bat type III IFNs are differentially induced relative to each other and to type I IFNs after treatment or transfection with synthetic dsRNA. Infection with the bat paramyxovirus, Tioman virus, resulted in no upregulation of type I IFN production in bat splenocytes but was capable of inducing a type III IFN response in three of the four bats tested. To our knowledge, this is the first report to describe the simultaneous suppression of type I IFN and induction of type III IFN after virus infection. These results may have important implications for the role of type III IFNs in the ability of bats to coexist with viruses.     

Interferons and interferon inhibitory activity in disease and therapy

Interferon (IFN) resistance is an important factor in the pathophysiology of neoplastic disorders, certain viral infections (e.g., AIDS), and autoimmune diseases (e.g., lupus erythematosus and Wegner's granulomatosis). In addition, in some of these disorders, there is also decreased ability to produce IFNs. The capacity of viruses and neoplastic processes to interfere with the IFN system are thought to represent a "virus-against-host" or "cancer-against-host" defense mechanism. Four resistance factors have been identified: 1) release of free IFN-alpha/beta type 1 receptors into the circulation that, at appropriate concentrations, capture and inactivate IFNs; 2) a new IFN inhibitory protein has been isolated and its chemical structure is under study; 3) prostaglandin E2, which is produced by certain tumor cells, inhibits IFN production; and 4) high levels of cAMP phosphodiesterases present, for example in certain tumor cells, reduces cAMP, an important second messenger in IFN synthesis. Studies are under way to reverse these inhibitory effects and to increase endogenous interferon production.     

Mechanisms of Antiviral Immune Evasion of SARS-CoV-2

Coronavirus disease (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is characterized by a delayed interferon (IFN) response and high levels of proinflammatory cytokine expression. Type I and III IFNs serve as a first line of defense during acute viral infections and are readily antagonized by viruses to establish productive infection. A rapidly growing body of work has interrogated the mechanisms by which SARS-CoV-2 antagonizes both IFN induction and IFN signaling to establish productive infection. Here, we summarize these findings and discuss the molecular interactions that prevent viral RNA recognition, inhibit the induction of IFN gene expression, and block the response to IFN treatment. We also describe the mechanisms by which SARS-CoV-2 viral proteins promote host shutoff. A detailed understanding of the host-pathogen interactions that unbalance the IFN response is critical for the design and deployment of host-targeted therapeutics to manage COVID-19.     

The interferons and their receptors--distribution and regulation

The interferons (IFNs) were originally described over 50 years ago, identified by their ability to confer viral resistance to cells. We now know that they are much more than just anti-viral cytokines collectively having roles in both innate and adaptive immune responses, in tumor surveillance and defense, and modulation of immune cell function. Three types of IFN have now been described, simply referred to as type I, II and III. Distinguishable by the unique receptors that they rely on for signal transduction, the three types of IFN have specific and varied roles in the maintenance of human health and defense against pathogens. In mounting an IFN-mediated immune response, the human body has developed the ability to regulate IFN-mediated signal transduction. Like all cytokines, the ability of a cell to respond to IFN is completely dependent on the presence of its cognate receptor on the surface of the target cell. Thus, one of the major mechanisms used by the human body to regulate the strength and duration of the IFN response is through regulation of receptor levels, thereby altering the cytokine-specific responsiveness of the target cell. This review will discuss the receptor system utilized by the type I IFNs and compare it with that of the type II and III IFNs, which also regulate immune responses through controlling receptor level on the cell surface.