The Essential Role of Type I Interferons in Differentiation and Activation of Tumor-Associated Neutrophils

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.

MYC Functions as a Switch for Natural Killer Cell-Mediated Immune Surveillance of Lymphoid Malignancies

“…MYC-driven lymphomagenesis 148 significantly increased numbers of pan CD11c + DCs and neutrophils (Supplementary Figures 149 4d-e). The increase in numbers of DCs and neutrophils during MYC-driven lymphomagenesis 150 corroborated the previously well-characterized pro-tumorigenic functions of these subsets in 151 lymphomas [18][19][20] . 152…”

DDX6 Represses Aberrant Activation of Interferon-Stimulated Genes

“…As a result, IFN-mediated homeostasis must be very tightly regulated, as prolonged or aberrant exposure is deleterious. Perturbations of IFN expression or signaling contribute to the etiology of several autoimmune diseases, dysregulated antiviral responses, and cancer (Corrales et al, 2017; Crow and Manel, 2015; Davidson et al, 2014; Pylaeva et al, 2016; Wilson et al, 2013). Many of these pathological conditions arise when PRRs inappropriately sense endogenous nucleic acids and it is now clear that aberrant nucleic acid metabolism and DNA damage are responsible for a multitude of autoimmune diseases (Crowl et al, 2017).…”

Cancer‐associated V‐ATPase induces delayed apoptosis of protumorigenic neutrophils

“…TANs survive longer than circulating neutrophils that allow TAN to promote tumor growth and metastasis (Fridlender and Albelda, ; Pylaeva et al , ; Queen et al , ). Studies suggest that TANs have long life span due to chemokines and growth factor presence in the TME (Clappaert et al , ; Sawanobori et al , ).…”

“…In agreement, we found that an increased neutrophil numbers in cancer tissues are associated with aggressive tumors based on the state of differentiation of cancer tissues. TANs survive longer than circulating neutrophils that allow TAN to promote tumor growth and metastasis (Fridlender and Albelda, 2012;Pylaeva et al, 2016;Queen et al, 2005). Studies suggest that TANs have long life span due to chemokines and growth factor presence in the TME (Clappaert et al, 2018;Sawanobori et al, 2008).…”

“…Also, a2NTD increases neutrophil recruitment to the site of the tumor (Ibrahim et al , ). The facts that protumorigenic TANs have long life span (Andzinski et al , ; Fridlender and Albelda, ; Pylaeva et al , ) and a2NTD enhances the protumorigenic properties of neutrophils (Ibrahim et al , ) led us to investigate the potential of a2NTD to regulate neutrophil survival.…”