ReviewInterferon-alpha in tumor immunity and immunotherapy
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”.
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