Type I Interferon in Chronic Virus Infection and Cancer

Abstract

Type I interferons (IFN-Is) are emerging as key drivers of inflammation and immunosuppression in chronic infection. Control of these infections requires IFN-I signaling; however, prolonged IFN-I signaling can lead to immune dysfunction. IFN-Is are also emerging as double-edged swords in cancer, providing necessary inflammatory signals, while initiating feedback suppression in both immune and cancer cells. Here, we review the proinflammatory and suppressive mechanisms potentiated by IFN-Is during chronic virus infections and discuss the similar, newly emerging dichotomy in cancer. We then discuss how this understanding is leading to new therapeutic concepts and immunotherapy combinations. We propose that, by modulating the immune response at its foundation, it may be possible to widely reshape immunity to control these chronic diseases.

Keywords: CD4 T cell; CD8 T cell; HCV; HIV; LCMV; T cell exhaustion; cancer; chronic virus; dendritic cell; immune activation; immunotherapy; innate immunity; interferon alpha; interferon beta; macrophage; persistent virus; tumor; type I interferon.

Figure 1.. Type I Interferons (IFN-Is) Promote and Inhibit Multiple Environmental and Cellular Functions to Modulate All Levels of Immunity during Viral Persistence and Cancer.

Most studies in chronic virus infections and cancer have focused on CD8 T cells and these cells are undoubtedly important in the inability of the immune system to overcome these diseases. However, CD8 T cells represent an endpoint of a complex set of cellular interactions, alterations in differentiation, and redirection of factors that underlie the global deterioration of multiple components of the immune response and ultimately lead to the attenuation of CD8 T cells and the failure to control these diseases. IFN-Is underlie many of the cellular functions and dysfunctions observed in chronic virus infections and this is also now beginning to come to light in multiple cancer types. IFN-Is promote immune maturation and differentiation from the innate to the adaptive immune response and, in times of chronic disease, also induce many of the immune dysfunctions throughout the immune response that impede virus and cancer control. These range of effects occur simultaneously throughout chronic viral infection and likely cancer, and ultimately represent a sliding scale dependent on many things, including the levels of IFN-Is, type of IFN-Is, duration of signaling, intracellular transcriptional programs, and other signals that cells are receiving. Abbreviations: MHC, major histocompatibility complex; Tfh, follicular helper T cell; Th, T helper cells; Treg, regulatory T cells.