title: CXCR2-mediated tumor-associated neutrophil recruitment is regulated by IFN-β.
abstract: The chemokine receptor CXCR2 and its ligands CXCL1, CXCL2 and CXCL5 play an important role in homing of tumor-associated neutrophils (TANs) into developing tumors. TANs are known to support the development of blood vessels in growing solid tumors, hence contributing to tumor growth. Here, we show that the migration of neutrophils is influenced by endogenous interferon-beta (IFN-β) via regulation of such chemokines and their receptor. We could demonstrate that CXCL1 and CXCL2 gradients are formed in tumor-bearing mice, i.e., low chemokine level in bone marrow (BM) and high level in the tumor. This supports migration of neutrophils into the tumor. Moreover, expression of CXCR2 was highest on neutrophils from BM and lowest in TANs. Importantly, although IFN-β appears to have only a minor influence on the expression of CXCR2, it strongly regulates the CXCR2 ligands. In the absence of endogenous IFN-β, they were expressed significantly higher in tumor-infiltrating neutrophils. Treatment of such neutrophils from tumor-bearing Ifnb1(-/-) mice with recombinant IFN-β downregulated CXCR2 ligand expression to wild-type levels. This explains the reduced migration of neutrophils into tumors and the diminished tumor angiogenesis in IFN-β-sufficient mice. Our results add a novel functional aspect of the type I IFN system as effector molecules of natural cancer surveillance and open interesting possibilities for antineutrophil therapies against cancer.
authors.affiliation: Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Jablonska
authors.forename: C-F
authors.initials: CF
authors.lastname: Wu
authors.forename: L
authors.initials: L
authors.lastname: Andzinski
authors.forename: S
authors.initials: S
authors.lastname: Leschner
authors.forename: S
authors.initials: S
authors.lastname: Weiss
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement; D054360:Chemokine CXCL1 / Q000235:genetics / Q000378:metabolism; D054426:Chemokine CXCL2 / Q000235:genetics / Q000378:metabolism; D054365:Chemokine CXCL5 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005354:Fibrosarcoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D005434:Flow Cytometry; D007124:Immunoenzyme Techniques; D016899:Interferon-beta / Q000502:physiology*; D008546:Melanoma, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012513:Sarcoma, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology*
chemical_list: D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D054365:Chemokine CXCL5; C475895:Cxcl1 protein, mouse; C404915:Cxcl2 protein, mouse; C094739:Cxcl5 protein, mouse; D012333:RNA, Messenger; D023063:Receptors, Interleukin-8B; D016899:Interferon-beta
keywords: IFN-β; chemokines; migration; neutrophils; tumor