Abstract

Type I interferons (IFNs) were first characterized in the process of viral interference. However, since then, IFNs are found to be involved in a wide range of biological processes. In the mouse, type I IFNs comprise a large family of cytokines. At least 12 IFN-α and one IFN-β can be found and they all signal through the same receptor (IFNAR). A hierarchy of expression has been established for type I IFNs, where IFN-β is induced first and it activates in a paracrine and autocrine fashion a cascade of other type I IFNs. Besides its importance in the induction of the IFN cascade, IFN-β is also constitutively expressed in low amounts under normal non-inflammatory conditions, thus facilitating “primed” state of the immune system. In the context of cancer, type I IFNs show strong antitumor function as they play a key role in mounting antitumor immune responses through the modulation of neutrophil differentiation, activation, and migration. Owing to their plasticity, neutrophils play diverse roles during cancer development and metastasis since they possess both tumor-promoting (N2) and tumor-limiting (N1) properties. Notably, the differentiation into antitumor phenotype is strongly supported by type I IFNs. It could also be shown that these cytokines are critical for the suppression of neutrophil migration into tumor and metastasis site by regulating chemokine receptors, e.g., CXCR2 on these cells and by influencing their longevity. Type I IFNs limit the life span of neutrophils by influencing both, the extrinsic as well as the intrinsic apoptosis pathways. Such antitumor neutrophils efficiently suppress the pro-angiogenic factors expression, e.g., vascular endothelial growth factor and matrix metallopeptidase 9. This in turn restricts tumor vascularization and growth. Thus, type I IFNs appear to be the part of the natural tumor surveillance mechanism. Here we provide an up to date review of how type I IFNs influence the pro- and antitumor properties of neutrophils. Understanding these mechanisms is particularly important from a therapeutic point of view.

Highlights

  • The significance of type I interferons (IFNs) in cancer immune surveillance is well established

  • This could be responsible for the inhibited migration of neutrophils into tumor tissue in WT animals, since they are trapped in the blood due to high concentration of CXCL5

  • All described mechanisms explain the increased migration of neutrophils into tumors leading to the enhanced tumor growth in IFN-deficient mice

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Summary

Frontiers in Immunology

Received: 30 September 2016 Accepted: 08 December 2016 Published: 21 December 2016. Type I interferons (IFNs) were first characterized in the process of viral interference. In the context of cancer, type I IFNs show strong antitumor function as they play a key role in mounting antitumor immune responses through the modulation of neutrophil differentiation, activation, and migration. Owing to their plasticity, neutrophils play diverse roles during cancer development and metastasis since they possess both tumor-promoting (N2) and tumor-limiting (N1) properties. Type I IFNs limit the life span of neutrophils by influencing both, the extrinsic as well as the intrinsic apoptosis pathways Such antitumor neutrophils efficiently suppress the pro-angiogenic factors expression, e.g., vascular endothelial growth factor and matrix metallopeptidase 9.

INTRODUCTION
THE PHENOTYPE OF NEUTROPHILS
IN NEUTROPHILS
REGULATION OF OXIDATIVE BURST BY TYPE I IFNs
AND IS INHIBITED BY TYPE I IFNs
ROS production by TAN
CONCLUDING REMARKS
AUTHOR CONTRIBUTIONS
Full Text
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