Abstract
During the last decades, the pleiotropic antitumor functions exerted by type I interferons (IFNs) have become universally acknowledged, especially their role in mediating interactions between the tumor and the immune system. Indeed, type I IFNs are now appreciated as a critical component of dendritic cell (DC) driven T cell responses to cancer. Here we focus on IFN-α and IFN-β, and their antitumor effects, impact on immune responses and their use as therapeutic agents. IFN-α/β share many properties, including activation of the JAK-STAT signaling pathway and induction of a variety of cellular phenotypes. For example, type I IFNs drive not only the high maturation status of DCs, but also have a direct impact in cytotoxic T lymphocytes, NK cell activation, induction of tumor cell death and inhibition of angiogenesis. A variety of stimuli, including some standard cancer treatments, promote the expression of endogenous IFN-α/β, which then participates as a fundamental component of immunogenic cell death. Systemic treatment with recombinant protein has been used for the treatment of melanoma. The induction of endogenous IFN-α/β has been tested, including stimulation through pattern recognition receptors. Gene therapies involving IFN-α/β have also been described. Thus, harnessing type I IFNs as an effective tool for cancer therapy continues to be studied.
Highlights
Type I interferons (IFNs) are pleiotropic immunomodulatory cytokines that were originally described based on their ability to interfere in the viral infection cycle [1], that is to say, activate protective antiviral machinery in infected cells, their neighbors and, on a systemic scale, in antigen presenting cells (APCs) and T lymphocytes [2]
Th1 cells are known for orchestrating cytotoxic T lymphocyte (CTL) responses that are implicated in the destruction of a tissue during autoimmune responses as well in antitumor responses [167], as demonstrated by a mechanistic degree of similarity shared between them [167, 168] and increased survival rate observed in patients with a CTL tumor infiltrate [169]. Another critical immunomodulatory mechanism induced by type I IFNs that directly affects T cell responses is the positive regulation of tumor antigens that are presented on cancer cells by MHC-I molecules, allowing the immune system to detect the tumor and distinguish it from a normal cell [170, 171]
There seems to be a paradoxical function of type I IFNs: early antiviral effects of type I IFNs are critical for host protection, promoting immune activation by stimulating an natural killer (NK) cell attack, enhancing dendritic cell (DC) antigen presenting function and favoring T cell proliferation, but after this adaptive immune response has been unleashed, chronic stimulation of the type I IFN pathway can result in immunoregulatory mechanisms that aim to shut down long lasting and unresolved immune responses, as discussed below, therapeutically induced IFN-α/β can restart or reinvigorate a new immunity cycle
Summary
Type I interferons (IFNs) are pleiotropic immunomodulatory cytokines that were originally described based on their ability to interfere in the viral infection cycle [1], that is to say, activate protective antiviral machinery in infected cells, their neighbors and, on a systemic scale, in antigen presenting cells (APCs) and T lymphocytes [2]. Spontaneous immune responses to tumor cells have been shown to depend on the activation of DCs by type I IFNs [15] and as a result, one of the first cancer immunotherapies ever to be approved by the US Food and Drug Administration (FDA) consisted of high doses of recombinant IFN-α2b for melanoma and renal cell carcinoma [16].
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