Interferons as cell-regulatory molecules

Cancer Immunol. Immunother. 7, 7-14 (1979) ancer mmunol9gyand mmunotherapy

© Springer-Verlag 1979

Review

Interferons as Cell-regulatory Molecules

F. R. Balkwill

Imperial Cancer Research Fund, Lincoln's Inn Field, London WC2A 3PX, England

Summary. This review presents the current evidence for interferons as cell-regulatory molecules. Apart from in- ducing an antiviral state, interferon preparations are powerful inhibitors of cell growth and have selective effects on cellular protein synthesis. In addition, interferons are produced during most immune reactions and can exert positive and negative influences on these reactions. Thus interferon molecules are of interest to cell biologists, immunologists, and oncologists. Interferon as a cell regulator offers a unique approach to cancer therapy, but for its judicious use, more understanding of basic mechamisms of action is required.

Introduction

The interferons, first discovered in 1957 [61] are a class of low-molecular-weight glycoproteins produced by many different cell types in response to virus infection and a variety of mitogenic or immunogenic stimuli. They are currently defined by their capacity to inhibit the growth of a wide range of viruses in cells of the same, or closely related, species, but are now also being recognized as an important group of hormone-like cell- regulatory molecules. A series ofinterferons, with differ- ences in antigenicity and physiochemical properties, has been identified (review [5]), and this article will discuss a role for these interferons in cell regulation.

lnterferons as Negative Growth Factors

As our understanding of the control of cell proliferation has increased, a number of positive growth factors have been discovered (review [35]), which can be extracted from serum or tissues or produced by cells in vitro, and

are capable of stimulating cells to synthesize DNA in chemically defined media. Although the importance of cell density and nutrient availability has been recognized in negative control of cell proliferation (review [57]), there is little information concerning substances that could be defined as negative growth factors. Chalones, a mainly theoretical group of noncytotoxic cell line-specific inhibitors, are still largely undefined [59, 93]. How- ever, the interferons are a group of naturally occurring molecules, which are capable of profound growth inhibition and probably represent the best characterized negative growth factors to date.

Originally when mouse L cell interferon was reported to inhibit cell growth in vitro [86], the impurity of the preparations cast doubt on the results [6], but since then interferons have been better purified and their growth-inhibitory capacity has been confirmed and shown to have many physicochemical properties identi- cal with the antiviral activities [14, 71, 102]. Moreover, mouse L cell interferon purified to homogeneity was shown to have cell growth-inhibitory activity [27]. How- ever, purification of the interferons has proved a difficult task, because their high specific activity means that they are produced in very small quantities, and the reader should note that this review will mainly describe work with interferon preparations containing some impuri- ties.

In the majority of tissue culture systems, interferon doses equivalent to 0.1 -~ 1 ng/ml purified material are capable of significant growth inhibition of a wide range of cell lines, strains, and primary cell cultures of normal or malignant origin [2, 4, 45, 86, 104]. This inhibition is primarily a reversible cytostatic effect [4, 45, 86]. Re- cent reports have suggested that growth inhibition by the interferons shows a degree of tissue specificity [29, 62], interferons from one tissue source being more inhibitory to cells of their tissue of origin than cells derived from other tissues.

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Mechanisms of Cell Growth Inhibition by the Interferons

Time-lapse cinematography showed that a mouse interferon exerted its cytostatic effect on routine EMT6 cells by a progressive increase of the cell cycle time [21] and some information concerning the effects of the interferons on specific phases of the cell cycle is now available. The majority of this evidence seems to indicate that interferons can lengthen all phases of the cell cycle, although the degree to which each is affected depends on the cell type studied: thus, Killander et al. [69] and Balkwill et al. [4] found that all phases of the cell cycle were lengthened in asynchronously dividing mouse leukemia and human breast cancer lines, respectively; Balkwill and Taylor-Papadimitriou [31 found G1 and S + G2 to be elongated in quiescent fibroblasts stimulated to divide; Matarese and Rossi [77] found that G1 and G2 were lengthened in interferon-treated Friend leukemia cells, while Fuse and Kuwata [34] and Sokawa et al. [98] reported that interferons only affected the G1 phase in human and mouse cells stimulated from quiescence.

There is little information concerning the effects of the interferons at a molecular level in non-virus-infected cells. In virus-infected cells it appears that they can act at many stages of the virus-replicative cycle, depending on the virus and cell system being investigated. For instance interferon treatment can cause inhibition of translation (reviews [90, 96], and transcription (review [85]) of viral mRNA and virus assembly and release [87]. Since 1964 it has been known that transcription and translation of a protein(s) are necessary for the estab- lishment of the antiviral state in interferon-treated cells [106], but this so-called antiviral protein has not yet been identified. Knight and Korant have recently ob- served that four distinct proteins are induced by interferon treatment [72], but the relevance of these to cell growth inhibition is unknown.

In cells treated with double-stranded RNA or interferon at least two enzyme systems are induced that affect translation of proteins in vitro: one is a synthetase, which produces an oligonucleotide with a 2'5' linkage that activates a latent endonuclease and inhibits protein synthesis by breakdown of message [68, 113]; the other is a protein kinase, which phosphorylates and thus inac- tivates the peptide chain initiation factor eIF2 and possibly other proteins [32]. However, the role of these two systems in the antiviral and cell growth-inhibitory effect of the interferons has yet to be elucidated.

No overall effect on cellular RNA and protein synthesis has been noted in interferon-treated uninfected cells [13, 101], but there are several reports of selective effects of interferons on certain proteins: for instance, Sreevalsan et al. found that mouse L cell interferon se-

F. R. Balkwilh Interferons as Cell-regulatory Molecules

lectively inhibited ornithine decarboxylase- and protein synthesis-dependent phosphate uptake in cells stimulated from quiescence [101]: rat interferon preparations specifically suppressed hormone-induced enzymes in rat hepatoma and glial cells with no overall effect on protein synthesis [7, 60]; chick interferon inhibited glutamine synthetase in chick normal retina cells without affecting other enzymes or total cellular protein synthesis [78]; and murine interferons inhibited transcription and translation of globin during erythroid differentiation of Friend leukemia cells in vitro [92]. The reason for these selective inhibitions by interferons is not known. Beck et al. suggested that proteins that are synthesized at a fast- er rate may be more inhibited by interferon action [71.

Interferons can also cause a variety of growth inhibitory effects in vivo: Administration of large doses of mouse sarcoma cell interferon inhibited the regeneration of mouse liver [33], and caused death in newborn mice if given during the first week of development [47]. Once again these effects were species-specific, human interferon having no effect in the murine experimental systems [47].

In summary, interferon preparations can inhibit cell growth in vitro by a reversible cytostatic effect that is manifest at concentrations attainable in vivo [80], and this effect is selective, the interferons being species- and possibly tissue-specific. The interferons can have selective inhibitory or enhancing effects on specific cell protein synthesis. Low concentrations of murine interferons stimulated globin synthesis and erythrocyte differentiation in Friend leukemia [76], and enhanced the polycy- clic hydrocarbon induction of aryl hydrocarbon hydroxylase activity in fetal mouse cultures [83]. In addition, murine interferons enhanced the expression of surface antigens [74].

These findings could indicate a regulatory role for the interferons in cell growth and differentiation, but more understanding of the relationship between the different types of interferons, and the stimuli that produce them, is required to clarify a role for interferons as negative growth factors in vivo.

Interferons and the Immune System

A role for the interferons in cell regulation is most con- vincingly demonstrated in studies of the immune system. In the course of various immune reactions, interferons are produced (type II or 'immune' interferons) (reviews [30, 114]), and exogenous interferons can have a number of enhancing or inhibitory effects on the immune system in vitro and in vivo (review [37]).

Although by definition they exert an anti-viral effect, type II interferons are produced by lymphocytes in re-

F. R. Balkwill: Interferons as Cell-regulatory Molecules

sponse to mitogenic [30, 66, 70, 111] and antigenic [36, 115, 89] stimulation. Type II interferons possess a variety of different physicochemical properties from type I (induced by viruses and double-stranded nucleotides): they are unstable at pH 2 [99, 115], have a higher molecular weight [99], and are antigenically distinct from type I interferons [31, 99, 114]. Data on which cells produce these types of interferon are confusing, and B cells, T cells, macrophages, and combinations of these have all been shown to produce type II interferons [30, 114]. It is possible that the sensitizing antigen may de- termine the producing cell.

As interferons are produced during the immune response and can modulate that response, they may be regarded as lymphokines. In the last 10 years, more than 50 soluble mediators of the immune response have been described (review [10]) and many of these lymphokines have properties similar to those of interferons [100]. However, rigorous purification procedures are required to elucidate the relationship between them. Inves- tigation of type II interferons is still at an early stage and all results with these preparations should be interpreted with caution as other mediators are probably present [18, 70, 115]. In describing the effects of exogenous interferons on the immune system we shall be primarily concerned with the better characterized type I interferons.

Interferons and the Humoral Immune System

High doses of type I interferons suppressed the primary and secondary response to a variety of T cell-dependent and -independent antigens in vivo and in vitro in mouse and human systems [11, 12, 64, 99] and prevented pas- sive cutaneous anaphylaxis in vivo by inhibiting Ig E production [84]. Recent reports indicated that partially purified preparations of type II interferons were more actively immunosuppressive than type I [99, 109].

There is some circumstantial evidence for a role for immune interferons in mediation of T cell suppression. T cell mitogens are potent inhibitors of the immune response, which act by stimulating suppressor cell activity, and these mitogens also stimulate the synthesis of type II interferon [63, 66]. The ability of a variety of these mitogens to inhibit in vitro antibody production was proportional to their ability to stimulate type II interferon production [63], and agents that blocked the production of mitogen-induced interferon also blocked the development of the suppressor state in an in vitro murine immune system [66].

Under certain conditions, interferons can have an immunoenhancing effect. Several workers have shown that the induction of interferon or addition of exogenous interferon to spleen cell cultures after the addition of antigen, enhanced the immune response [11, 12, 65], as

did low doses of interferon given in vivo [11]. Type II interferons can also have enhancing effects, depending on the time of administration and the dosage, but this enhancing effect has only been found for T-dependent antigens [109]. Interferon preparations also enhanced IgE-mediated histamine release from human peripheral blood cells in vitro and this enhancement required de novo protein synthesis [53].

Interferons and Cell-mediated Immunity

A temporary decrease in cell-mediated immunity is a common side effect in virus infections, and there is now evidence that this is due to interferon production (review [23]). The most dramatic effects of interferons have been on the development of delayed-type hypersensitivity: De Maeyer et al. found that administration of high doses of interferon prior to sensitization of mice prevented the development of an immune response, and that interferon administration to sensitized animals be- fore challenge with the sensitizing antigen prevented the development of hypersensitivity [25, 26]. Type I interferons also suppressed the rejection of allogeneic skin grafts in mice [24] and modified graft-versus-host responses [56]. In vitro, some mitogen-induced lymphocyte blastogenesis [75, 82] and the mixed lymphocyte reaction [9, 26, 54] were inhibited by the addition of interferons, although enhancement of mitogenesis has also been reported [2, 82].

In contrast to the suppressive effects reported above, interferons can have remarkable enhancing activities on some of the effector cells in the cell-mediated immune system.

Mouse L cell interferon enhanced the specific cytotoxicity of sensitized murine lymphocytes for allogeneic target cells in vitro [73], and in a human system, although the mixed lymphocyte reaction was inhibited by interferon, the resulting sensitized lymphocytes had greatly increased cytotoxic potential [54].

There is increasing evidence that the natural killer (NK) cell is an important component of host-mediated defence against tumours (review [8]). This cell can be activated in vivo and in vitro by a variety of agents [51, 107, 110] that have a common property of being interferon inducers. Moreover, exogenous interferons caused a rapid increase in murine spleen NK cell activity in vivo [22, 97] and spleen or peripheral blood NK cells in vitro [52, 55]. Further evidence for a central role for interferons in activating and enhancing NK cells comes from elegant studies by Trinchieri and his colleagues. They showed that lymphocyte cultures produced an interferon during 'recognition' and lysis of human cells, and that this interferon was capable of enhancing NK activity [107, 108]. Herberman et al. have reported that inter-

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ferons can also enhance antibody-dependent cell killing [52].

Interferons are also known to affect macrophage function: interferon preparations or inducers enhanced the phagocytic activity of murine maerophages in vivo and in vitro [28, 50] and rendered mouse macrophages cytotoxic to a leukemia cell line in vitro [95]. There is some evidence that macrophage-activating 'Factors' in lymphokine preparations have the characteristics of interferons [94], suggesting that, as with the NK cell, interferons may be a regulator of macrophage activation.

Little is known about the importance of production in vivo, but there are reports of low immune interferon production associated with decreased resistance to infection in chronic lymphocytic leukaemia patients [31] and in patients with IgA deficiency [67].

Thus interferon preparations have a bewildering array of modulating effects on the immune system in vivo and in vitro. As a generalization, interferons appear to inhibit the sensitizing and proliferative pathways of the immune response and enhance the effector pathways, thus moderating the growth of stimulated clones while enhancing the activity of any effector cells produced. Of central importance in clarifying a role for interferons in immune regulation is the purification and characterization of the interferon-like lymphokines produced during the immune response.

Interferons and Cancer

Soon after the discovery of interferons, Atanasiu and Chany reported that prior administration of interferon inhibited the development of polyoma induced neoplasms in newborn hamsters [i]. This work was repeated with a variety of oncogenic virus systems in experimental animals (review [41]), and interferons were also found to delay the progression of established virus induced neoplasms such as the Friend [42, 112] and Rauscher [43] murine leukemias, and Herpesvirus saimiri induced leukaemia in owl monkeys [88].

Protective effects of interferons have also been reported for a range of 'spontaneous' murine cancers in which a viral aetiology is implicated (review [41]). For example, Gresser et al. [44] reported that long-term treatment of newborn AKR mice with mouse brain interferon significantly increased their survival time and diminished their incidence of leukaemia. These workers also found that interferon treatment commenced after the diagnosis of lymphoma increased the average survival of mice by 100% in a disease where many conventional chemotherapeutic agents had little effect [48]. Came and Moore found that interferons or interferon inducers inhibited the rate of development of spontaneous murine mammary cancinomas although no decrease of virus production in milk could be found [15].


In all the experiments reported above, it is conceiv- able that the major effect of interferon was mediated by inhibition of oncogenic virus replication and cell trans- formation, but work with transplantable tumours has indicated that other effects of interferons may be important. In 1970, Gresser reported that repeated administration of mouse brain interferon significantly increased the survival of mice transplanted with syngeneic tumour cells [38], and later work showed that exogenous interferon markedly reduced the growth of the syngeneic murine Lewis lung carcinoma and the development of pulmonary metastases [39].

All the antitumour effects described above have been mediated by type I interferons. One recent report has compared the effect of murine type I and type II interferons on the development of syngeneic transplantable osteogenic sarcoma. Type II interferons were 100-fold more active than type I, and even when given in ex- tremely small doses, could have dramatic effects on tumour development [19].

One promising experimental approach has been to combine interferon therapy with standard chemotherapeutic agents. Chirigos and Pearson found that a murine interferon administered after BCNU-induced remission in a murine leukaemia displayed synergism with the drug, significantly increased the 'cure' rate, and doubled the survival time of affected mice [17]. More recently, Gresser et al. have reported that combined therapy with cyclophosphamide and C-243 cell interferon in mice with AKR lymphoma doubled the survival time obtained with either agent alone [49].

Therefore, interferon treatment in experimental ani- mal neoplasms, whether of virus, spontaneous, or transplantable origin, delayed the progression of the disease but only in very few cases have 'cures' been reported.

Extension of these studies to human cancer has proved difficult because of the limited quantities of human interferons available. The major source of human interferon to date has been a type I interferon induced in blood bank leucocytes by Sendai virus [16]. More recently, limited quantities of fibroblast interferon have been made [58]. A promising source soon to be available for clinical trials is an interferon derived from human lymphoblastoid cells, which can be produced commercially in large quantities (N. Finter, personal communication).

In 1971, Strander and his colleagues began to use human leucocyte interferon as postoperative adjuvant therapy in osteogenic sarcoma patients, their survival being compared with concurrent controls treated at other hospitals in Sweden. Results so far [103] indicate that 60% of the 24 interferon-treated patients were free of detectable metastases at 2 years, compared with 25% of 35 control patients. The design of the trial precludes


conclusive statistical analysis at this time, but the results are encouraging. Pilot studies have been carried out on a small number of patients with easily monitorable disease. Merigan and his colleagues studied the response of six non-Hodgkin's lymphoma patients to human leucocyte interferon therapy. While no effect was seen in three patients with previously treated, rapidly advancing histiocytic lymphoma, three patients with previously untreated, poorly differentiated lymphocytic lymphoma showed regression of the disease, and in two of these the disease was stabilized for 6 months after a 30-day treatment [81]. The Swedish workers have recently described human leucocyte interferon therapy of four patients with previously untreated myelomatosis [79]. In all patients progression of the disease was halted and in two patients complete remission was obtained [79]. Other human cancer studies are, in general, anecdotal, with treatment of single patients for short periods of time (review [104]) and results that are variable and difficult to interpret.

It is of interest to note that in these studies the side effects of interferon therapy were not severe. The major effects noted were fever, mild malaise, and leucopoenia [79, 81]. A beneficial side effect noted in the osteogenic sarcoma was that patients showed less evidence of acute viral infections than their immediate family [105].

Properly controlled clinical trials with adequate numbers of patients are now necessary, and with the impending availability of large quantities of human lymphoblastoid interferon it is hoped this will be possible. Meanwhile, a preliminary approach to selecting suitable cancers for interferon therapy, especially where tumour cells cannot be grown in vitro, is to study the effects of human interferon on the growth of human tumour xenografts in the nude mouse. Two recent reports using human cell lines as xenografts have not been encouraging [20, 58]; however, recent work from our laboratory (F. R. Balkwill et al., submitted for publication) has shown that the development and growth of two of three primary human breast carcinomas in nude mice was significantly inhibited by human lymphoblastoid interferon treatment.

Therefore a role for interferons in the treatment of human cancer is, as yet, uncertain, like the mechanism(s) of the turnout inhibitory effect seen in experimental animals and the few documented human cases. This review has described several ways in which the interferons could act as turnout inhibitors and the pre- dominating mechanism for a particular tumour could depend on its unique neoplastic character.

There is a certain amount of evidence for a role for interferons in enhancing host responses to the tumour. Gresser et al. found that a transplantable L 1210 leukaemia that was resistant in vitro to the growth-inhibitory effects of a mouse interferon could still be inhibited in vivo, although not to as great an extent as a line that

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was sensitive in vitro [46]. Secondly, these workers reported extensive phagocytosis of tumour cells by macrophages in interferon-treated mice [38]. In addition, lymphocytic infiltration of human fibroblast interferon- treated melanoma metastases has been recorded [58]. Another theoretical way in which interferon can favour- ably influence a host reaction to a tumour has been suggested by Rosenfeldt to explain the effects of interferon therapy in myelomatosis patients. His theory was that myelomatosis may be caused by defect in a T cell suppressor population, allowing abnormal expansion of a B cell clone, and that interferon therapy may correct that defect [29]. It is of interest that the favourable results with interferon therapy in human cancer have been obtained in immunocompetent host [79, 81, 103].

However, it is unlikely that enhancement of host reactions are responsible for all the anti-tumour activity of the interferons. For instance, the data demonstrating inhibition of human breast cancer xenografts in nude mice (F. R. Balkwill et al., submitted for publication) seem to indicate that at least in this 'artificial' situation, interferon can have a direct effect on tumour cells, as human interferon would not be expected to affect a mu- fine immune response. In addition, Gresser and Bourali- Maury reported that the antitumour effect of interferons in murine transplantable tumours was not abro- gated by pretreatment with anti-lymphocyte serum (ALS) or X-irradiation, although silica treatment, which destroys macrophages, diminished somewhat interferon's antitumour activity [40].

It is so far apparent that interferon treatment per se rarely cures neoplastic disease, but it delays its progression, and shifts the balance between tumour and host in favour of the host. From the data discussed in this review it can be seen that interferons may alter this host- tumour relationship by a variety of mechanisms: not only by inhibition of viral oncogenesis and possible re- cruitment to the transformed clone; but also by enhancing host immune effector cell activity against the tumour; enhancing surface antigen expression (and thus host responses); and by acting as a chalone-like negative growth factor.

Much further work is needed to evaluate the importance of the regulatory functions of the interferons to cancer therapy in man. The main priorities are plentiful supplies of interferon and carefully controlled work in patients in which disease and host response can be mon- itored.

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Received July 10, 1979

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Interferons as cell-regulatory molecules