title: IRF-1 expression is essential for natural killer cells to suppress metastasis.
abstract: IFN-γ promotes tumoral immune surveillance, but its involvement in controlling metastases is less clear. Using a mouse model of pulmonary metastases, we show that local IFN-γ treatment inhibits formation of metastases through its regulation of IRF-1 in tumor cells. IRF-1 is an IFN-γ-induced transcription factor pivotal in the regulation of infection and inflammation. IRF-1 blockade abolished the inhibitory effect of IFN-γ on tumor metastases, whereas ectopic expression of IRF-1 phenocopied the inhibitory effects of IFN-γ. IRF-1 did not affect the survival of tumor cells in the circulation or their infiltration into lungs, but it was essential to support the pulmonary attraction and activation of natural killer (NK) cells. Depleting NK cells from mice abolished the protective effect of IFN-γ or IRF-1 on metastases. In addition, cytotoxicity assays revealed that tumor cells expressing IRF-1 were targeted more effectively by NK cells than IRF-1 nonexpressing tumor cells. Moreover, NK cells isolated from lungs inoculated with IRF-1-expressing tumor cells exhibit a greater cytotoxic activity. Mechanistic investigations revealed that IRF-1-induced NK cell cytotoxicity was independent of perforin and granzyme B but dependent on the NK cell activating receptor DNAM-1. Taken together, our findings establish IRF-1 as an essential mediator of the cross-talk between tumor cells and NK cells that mediate immune surveillance in the metastatic niche.
authors: Department of Gene Regulation and Differentiation, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors: Antje
authors: A
authors: Ksienzyk
authors: Berit
authors: B
authors: Neumann
authors: Ramya
authors: R
authors: Nandakumar
authors: Katja
authors: K
authors: Finsterbusch
authors: Martina
authors: M
authors: Grashoff
authors: Rainer
authors: R
authors: Zawatzky
authors: Günter
authors: G
authors: Bernhardt
authors: Hansjörg
authors: H
authors: Hauser
authors: Andrea
authors: A
authors: Kröger
mesh_terms: D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D002277:Carcinoma / Q000188:drug therapy / Q000276:immunology* / Q000556:secondary; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D053804:Granzymes / Q000494:pharmacology; D050856:Interferon Regulatory Factor-1 / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D054353:Perforin / Q000494:pharmacology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology; D011991:Receptors, Virus / Q000276:immunology; D015854:Up-Regulation; D000098862:T Lineage-Specific Activation Antigen 1
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D000098862:T Lineage-Specific Activation Antigen 1; D050856:Interferon Regulatory Factor-1; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D011991:Receptors, Virus; C066100:poliovirus receptor; D054353:Perforin; D007371:Interferon-gamma; D053804:Granzymes