Type I interferon-mediated polarization of neutrophils and its impact on cancer progression and bacterial infections

Abstract

Neutrophils constitute the main leukocyte population in the human blood. Due to their abundance, rapid mobilization and potent cytotoxic properties (release of reactive oxygen species (ROS), bactericidal proteins and neutrophil extracellular traps (NETs), neutrophils become the first line of immune response during infection and inflammation. In tumor situation, neutrophils gain new properties due to the influence of specific tumor-microenvironment, and regulate tumor angiogenesis and metastasizing, as well as anti-tumor immune responses. Neutrophil functionality is regulated by many factors, but type I interferons (IFNs) are one of the most potent cytokines in this context. It could be shown here that the presence of IFNs stimulates pro-inflammatory activity of neutrophils, while in the absence of interferons neutrophils develop anti-inflammatory, regenerative capacity. In the context of tumor, type I IFNs stimulate anti-tumor (N1) polarization of neutrophils. It was recently shown that during cancer progression, the signaling via type I IFNs receptor (IFNAR) is suppressed, due to the degradation of IFNAR in tumor tissue. . This results in the establishment of immune suppressive microenvironment in tumor and supports tumor progression. Here, the effect of such disbalance of IFN availability on neutrophil pro-tumor functions was analyzed. It could be demonstrated that the absence of type I IFNs signaling at the tumor site triggers pro-tumor polarization and nicotinamide phosphoribosyltransferase (NAMPT)-dependent proangiogenic switch of tumor-associated neutrophils, resulting in elevated tumor angiogenesis and growth. Inhibition of NAMPT signaling in TANs leads to their anti-tumor activation with decreased angiogenic activity. Transfer of such anti-tumor neutrophils into tumor-bearing mice was demonstrated to have a therapeutic suppressive effect on tumor growth. In the context of bacterial infections, the upregulation of IFN signaling at the periphery results in the overactivation of neutrophils and their elevated release of Neutrophil Extracellular Traps (NETs). Accumulation of NETs in lung tissue during infection with Pseudomonas (P.) aeruginosa supports survival of bacteria, which could use such NETs as a scaffold for creating biofilms that protect them from the immune system and antibiotics. Prevention of NETs formation by activated lung neutrophils using N-acetylcysteine (NAC) or deoxyribonuclease (DNase) limits tissue damage and reduces bacterial persistence in the lung. In summary, the essential role of type IFNs in the regulation of neutrophil activity could be here demonstrated, both during bacterial infections as well as during cancer progression. Changes of neutrophil functions may serve as potential diagnostic marker for disease progression or development of complications. Based on the results of the study, the new potential therapeutic targets can be identified to improve the disease treatment.