title: Type I interferon is selectively required by dendritic cells for immune rejection of tumors.
abstract: Cancer immunoediting is the process whereby the immune system suppresses neoplastic growth and shapes tumor immunogenicity. We previously reported that type I interferon (IFN-α/β) plays a central role in this process and that hematopoietic cells represent critical targets of type I IFN's actions. However, the specific cells affected by IFN-α/β and the functional processes that type I IFN induces remain undefined. Herein, we show that type I IFN is required to initiate the antitumor response and that its actions are temporally distinct from IFN-γ during cancer immunoediting. Using mixed bone marrow chimeric mice, we demonstrate that type I IFN sensitivity selectively within the innate immune compartment is essential for tumor-specific T cell priming and tumor elimination. We further show that mice lacking IFNAR1 (IFN-α/β receptor 1) in dendritic cells (DCs; Itgax-Cre(+)Ifnar1(f/f) mice) cannot reject highly immunogenic tumor cells and that CD8α(+) DCs from these mice display defects in antigen cross-presentation to CD8(+) T cells. In contrast, mice depleted of NK cells or mice that lack IFNAR1 in granulocytes and macrophage populations reject these tumors normally. Thus, DCs and specifically CD8α(+) DCs are functionally relevant targets of endogenous type I IFN during lymphocyte-mediated tumor rejection.
authors.affiliation: Department of Pathology and Immunology, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Diamond
authors.forename: Michelle
authors.initials: M
authors.lastname: Kinder
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Matsushita
authors.forename: Mona
authors.initials: M
authors.lastname: Mashayekhi
authors.forename: Gavin P
authors.initials: GP
authors.lastname: Dunn
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Archambault
authors.forename: Hsiaoju
authors.initials: H
authors.lastname: Lee
authors.forename: Cora D
authors.initials: CD
authors.lastname: Arthur
authors.forename: J Michael
authors.initials: JM
authors.lastname: White
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kalinke
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Murphy
authors.forename: Robert D
authors.initials: RD
authors.lastname: Schreiber
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002678:Chimera; D045142:Cross-Priming / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D006098:Granulocytes / Q000276:immunology; D007113:Immunity, Innate / Q000276:immunology; D007370:Interferon Type I / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: C508032:Ifnar1 protein, mouse; D007370:Interferon Type I; D053633:Receptor, Interferon alpha-beta; D007371:Interferon-gamma