Review
Interferon-alpha in tumor immunity and immunotherapy

https://doi.org/10.1016/S1359-6101(01)00022-3Get rights and content

Abstract

Interferon-alpha (IFN-α) is a pleiotropic cytokine belonging to type I IFN, currently used in cancer patients. Early studies in mouse tumor models have shown the importance of host immune mechanisms in the generation of a long-lasting antitumor response to type I IFN. Recent studies have underscored new immunomodulatory effects of IFN-α, including activities on T and dendritic cells, which may explain IFN-induced tumor immunity. Reports on new immune correlates in cancer patients responding to IFN-α represent additional evidence on the importance of the interactions of IFN-α with the immune system for the generation of durable antitumor response. This knowledge, together with results from studies on genetically modified tumor cells expressing IFN-α, suggest novel strategies for using these cytokines in cancer immunotherapy and in particular the use of IFN-α as an immune adjuvant for the development of cancer vaccines.

Introduction

Interferons-alpha (IFNs-α) are proteins belonging to type I IFN, currently used in cancer therapy [1], [2]. Type I IFN was discovered almost 45 years ago by its capability to inhibit virus replication. Although low levels of type I IFN are detected under physiological conditions, production is markedly enhanced during infections [3]. Today, human type I IFN includes the IFN-α family of at least 13 functional subtypes of IFN-α, IFN-beta (IFN-β), and IFN-omega (IFN-ω) [4]. The different IFN-α subtypes share the same receptor system [4] and exhibit similar biological activities, even though the existence of different natural subtypes may reflect still unknown in vivo functions. More than 40 years of research on IFN-α have revealed that this cytokine exhibits a variety of other biological effects different from those on viral replication, including antitumor activity [2]. Today, IFN-α is the most used cytokine in patients [1], [2]. IFN-α is used in over 40 countries for the treatment of more than 14 types of cancer, including some hematological malignancies (hairy cell leukemia, chronic myeloid leukemia, some B and T cell lymphomas) and certain solid tumors, such as melanoma, renal carcinoma and Kaposi’s sarcoma. However, in spite of many years of intense work in animal tumor models and considerable experience in the clinical use of IFN, the important mechanisms underlying the antitumor response are not fully understood. Likewise, little is known about why some tumors are highly responsive to IFN treatment, while others show little or no response.

For a long time, it was thought that the direct inhibitory effects on tumor cell growth/functions were the major mechanisms important in the antitumor response in patients. In fact, IFN-α can directly inhibit the proliferation of normal and tumor cells in vitro and in vivo, and can exert other direct effects on tumor cells. These effects include the down-regulation of oncogene expression and induction of tumor suppressor genes, which can contribute to the antiproliferative activity of this cytokine, and the increase of MHC class I expression, which can enhance immune recognition [2]. Curiously, in several human neoplasms which have shown the most striking clinical benefit (e.g. melanoma), little direct inhibitory activity can be demonstrated at clinically achievable dosage concentrations. In addition to the direct effects on tumor cells, type I IFN exerts several effects on host immune cells that play a more central role in the overall antitumor response [3], [5]. The importance of these effects was originally demonstrated in early studies of mice transplanted with IFN-resistant tumor cells [5]. However, the possible clinical implications of those early studies that described the immune mechanisms in IFN-treated tumor-bearing mice were underappreciated. In subsequent years, the use of genetically modified tumor cells expressing IFN-α in murine models resulted in further characterization of the antitumor immune mechanisms elicited by the local production of IFN-α at the tumor site [6]. These results, together with emerging knowledge on previously unrecognized effects of type I IFN on immune cells in both mouse models and humans [5], [6], can lead to the recognition of the importance of these cytokines in tumor immunity. While the role of the host immune system in the IFN-α-induced response in patients was largely neglected in the past [5], recent clinical studies reveal new immune correlates of clinical response which might be predictive of antitumor efficacy [7], [8]. This article summarizes the current knowledge on the role of IFN-α in tumor immunity and immunotherapy and reviews the most relevant studies from several laboratories, including ours, in the context of recent data supporting the importance of this cytokine in the initiation and regulation of the immune response. We begin this review by providing a brief overview of the most important clinical trials with IFN-α in patients with melanoma, since the use of this cytokine as a single agent in the adjuvant therapy of melanoma has led to a relevant response. Furthermore, metastatic melanoma represents an ideal target of cancer immunotherapy. We then review recent data highlighting the role of IFN-α as a “bridge system” connecting innate and adaptive immunity. This knowledge can be useful in interpreting recent results in both mouse tumor models and cancer patients and in understanding the historical importance of early studies in mice as well as in designing new strategies of cancer immunotherapy.

Section snippets

Risk groupings and adjuvant therapy in melanoma

The risk of relapse and death following resection of local/regional involvement with cutaneous melanoma determines the need for consideration of adjuvant therapy. The risk of primary melanoma can be accurately predicted on the basis of the T, N, and M criteria recently adopted by the American Joint Commission on Cancer (AJCC) for staging primary and regional nodal disease as published [9], [10]. The pooled results of >16,700 patients serve as the basis for the new refined AJCC criteria for

The importance of the host immune system in the antitumor response to type I IFN: lessons from mouse tumor models

Immunocompetent mice transplanted with immunogenic syngeneic tumors have represented practical in vivo models for evaluating the effects of cytokines on the generation of humoral and cellular immunity directed against tumor specific antigens. We will now briefly review some early studies on the role of the host immune system in the antitumor effects of type I IFN in mice, which showed the importance of the immune system in determining an effective and long-lasting antitumor response to IFN.

IFN-α gene transfer and antitumor immune response

Over the last decade, cytokine gene transfer into tumor cells has been regarded as a useful approach for the treatment of some human malignancies [61] as well as a more physiological strategy for the activation of an antitumor immune response as compared with systemic administration of cytokines. In fact, systemic administration of cytokines at pharmacologic doses, in addition to being associated with severe toxicity, results in a high concentration of cytokines in the circulation and often in

Clinical response to treatment with IFN-α and the host immune response

The involvement of immune mechanisms in the therapeutic effect of IFN-α in cancer patients has been barely investigated. This is surprising considering the evidences of the importance of the host immune system in the antitumor activity of type I IFN in experimental tumor models, as well as interesting observations of modulation of the immune response during IFN-α therapy in cancer patients that were reported since the early 1980s. Table 3 summarizes selected reports describing immune correlates

Conclusions and perspectives

In this article, we have reviewed early and recent studies in both tumor models and in patients with cancer highlighting the importance of IFN-α in tumor immunity and immunotherapy. IFN-α has achieved a long record of clinical use in cancer patients [1], [2]. “Second generation type I IFNs”, including pegylated IFN-α and new synthetic IFN molecules, are available for clinical testing with the hope of developing even more effective molecules for cancer treatment. However, we believe that much

Acknowledgements

We are grateful to Ion Gresser not only for his fundamental contribution to the identification of the host immune mechanisms involved in the antitumor effects of type I IFN in mice, but also for his precious friendship, discussions and encouragement over the years. We thank Mrs. Anna Ferrigno for secretarial assistance and Mrs. Maria Bond for the help in preparing this manuscript. Work in the authors’ laboratory was supported by grants provided by AIRC and the “Italy–USA Program on Tumors”.

References (105)

  • F. Belardelli

    Role of interferons and other cytokines in the regulation of the immune response

    APMIS

    (1995)
  • K.E. Mogensen et al.

    Type I IFN receptor: structure, function, and evolution of a family business

    J Interferon Cytokine Res.

    (1999)
  • Wu JC, Yang X-F, McLaughlin S, et al. Detection of a potent humoral response associated with immune-induced remission...
  • Molldrem JJ, Lee PP, Wang C, et al. Evidence that specific T lymphocytes may participate in the elimination of chronic...
  • Balch CM, Buzaid AC, Atkins MB, et al. A new American Joint Committee on Cancer staging system for cutaneous melanoma....
  • Balch CM, Soong S, Gershenwald JE, et al. Prognostic factors analysis of 17,600 melanoma patients. Validation of the...
  • Livingston PO, Wong GYC, Adluri S, et al. Improved survival in stage III melanoma patients with GM2 antibodies: a...
  • J.M. Kirkwood et al.

    Interferon-alpha-2b adjuvant therapy of high-risk resected cutaneous melanoma: The Eastern Cooperative Oncology Group Trial EST 1684

    J. Clin. Oncol.

    (1996)
  • J.M. Kirkwood et al.

    Pooled-analysis of four ECOG/intergroup trials of high-dose interferon-alpha-2b (HDI) in 1916 patients with high-risk resected cutaneous melanoma

    Proc. ASCO

    (2001)
  • Creagan ET, Dalton RJ, Ahmann DL, et al. Randomized, surgical adjuvant clinical trial of recombinant...
  • Kirkwood JM, Ibrahim JG, Sondak VK, et al. High- and low-dose interferon-alpha-2b in high-risk melanoma: first analysis...
  • Kirkwood JM, Ibrahim J, Lawson DH, et al. High-dose interferon-alpha-2b does not diminish antibody response to GM2...
  • Morton DL, Foshag LJ, Hoon DS, et al. Prolongation of survival in metastatic melanoma after active specific...
  • Reintgen D, Cruse CW, Wells K, et al. The orderly progression of melanoma nodal metastases. Ann Surg...
  • M.I. Ross et al.

    Selective lymphadenectomy: emerging role of lymphatic mapping and sentinel node biopsy in the management of early stage melanoma

    Semin. Surg. Oncol.

    (1993)
  • N. Cascinelli

    Evaluation of efficacy of adjuvant rIFN-α2a in melanoma patients with regional node metastases

    Proc. ASCO

    (1995)
  • Pehamberger H, Soyer P, Steiner A, et al. Adjuvant interferon-alpha-2a treatment in resected primary stage II cutaneous...
  • Kirkwood JM. Interferon-alpha and -beta: clinical applications: melanoma. In: Rosenberg SA, editor. Principles and...
  • Rogge L, Barberis-Maino L, Biffi M, et al. Selective expression of an interleukin-12 receptor component by human T...
  • Tüting T, Wilson CC, Martin DM, et al. Autologous human monocyte-derived dendritic cells genetically modified to...
  • C.C. Wilson et al.

    HIV-1-specific CTL responses primed in vitro by blood-derived dendritic cells and Th1-biasing cytokines

    J. Immunol.

    (1999)
  • K. Hirohishi et al.

    IFN-α-expressing tumor cells enhance generation and promote survival of tumor-specific CTLs

    J. Immunol.

    (2000)
  • K.J. Palmer et al.

    Interpheron-alpha (IFN-α) stimulates anti-melanoma cytotoxic T lymphocyte (CTL) generation in mixed lymphocyte tumor cultures (MLTC)

    Clin. Exp. Immunol.

    (2000)
  • D.F. Tough et al.

    Induction of bystander T cell proliferation by viruses and type I interferon in vivo

    Science

    (1996)
  • S. Sun et al.

    Type I interferon-mediated stimulation of T cells by CpG DNA

    J. Exp. Med.

    (1998)
  • P. Marrack et al.

    Type I interferons keep activated T cells alive

    J. Exp. Med.

    (1999)
  • R.M. Steinman

    The dendritic cell system and its role in immunogenicity

    Annu. Rev. Immunol.

    (1991)
  • Paquette RL, Hsu NC, Kiertscher SM, et al. Interferon-alpha and granulocyte-macrophage colony-stimulating factor...
  • Luft T, Pang KC, Thomas E, et al. Type I IFNs enhance the terminal differentiation of dendritic cells. J Immunol...
  • L.G. Radvanyi et al.

    Low levels of interferon-alpha induce CD86 (B7.2) expression and accelerates dendritic cell maturation from human peripheral blood mononuclear cells

    Scand. J. Immunol.

    (1999)
  • Santini SM, Lapenta C, Logozzi M, et al. Type I interferon as a powerful adjuvant for monocyte-derived dendritic cell...
  • Siegal FP, Kadowaki N, Shodell M, et al. The nature of the principal type I interferon-producing cells in human blood....
  • Cella M, Jarrossay D, Facchetti F, et al. Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large...
  • F. Belardelli et al.

    Antitumor effects of interferon in mice injected with interferon-sensitive and interferon-resistant Friend leukemia cells I

    Int. J. Cancer

    (1982)
  • F. Belardelli et al.

    Antitumor effects of interferon in mice injected with interferon-sensitive and interferon-resistant Friend leukemia cells. II. Role of host mechanisms

    Int. J. Cancer

    (1982)
  • F. Belardelli et al.

    Antitumor effects of interferon in mice injected with interferon-sensitive and interferon-resistant Friend leukemia cells. III. Inhibition of growth and necrosis of tumor implanted subcutaneously

    Int. J. Cancer

    (1983)
  • I. Gresser et al.

    Antitumor effects of interferon in mice injected with interferon-sensitive and interferon-resistant Friend leukemia cells. IV. Definition of optimal treatment regimens

    Int. J. Cancer

    (1986)
  • I. Gresser et al.

    Antitumor effects of interferon in mice injected with interferon-sensitive and interferon-resistant Friend leukemia cells. VI. Adjuvant therapy after surgery in the inhibition of liver and spleen metastases

    Int. J. Cancer

    (1987)
  • Gresser I, Maury C, Woodrow D, et al. Interferon treatment markedly inhibits the development of tumor metastases in the...
  • I. Gresser et al.

    Antitumor effects of interferon in mice injected with interferon-sensitive and interferon-resistant Friend erythroleukemia cells. VIII. Role of the immune system in the inhibition of visceral metastases

    Int. J. Cancer

    (1990)
  • Cited by (0)

    View full text