title: Antitumor NK activation induced by the Toll-like receptor 3-TICAM-1 (TRIF) pathway in myeloid dendritic cells.
abstract: Myeloid dendritic cells (mDCs) recognize and respond to polyI:C, an analog of dsRNA, by endosomal Toll-like receptor (TLR) 3 and cytoplasmic receptors. Natural killer (NK) cells are activated in vivo by the administration of polyI:C to mice and in vivo are reciprocally activated by mDCs, although the molecular mechanisms are as yet undetermined. Here, we show that the TLR adaptor TICAM-1 (TRIF) participates in mDC-derived antitumor NK activation. In a syngeneic mouse tumor implant model (C57BL/6 vs. B16 melanoma with low H-2 expresser), i.p. administration of polyI:C led to the retardation of tumor growth, an effect relied on by NK activation. This NK-dependent tumor regression did not occur in TICAM-1(-/-) or IFNAR(-/-) mice, whereas a normal NK antitumor response was induced in PKR(-/-), MyD88(-/-), IFN-beta(-/-), and wild-type mice. IFNAR was a prerequisite for the induction of IFN-alpha/beta and TLR3. The lack of TICAM-1 did not affect IFN production but resulted in unresponsiveness to IL-12 production, mDC maturation, and polyI:C-mediated NK-antitumor activity. This NK activation required NK-mDC contact but not IL-12 function in in vivo transwell analysis. Implanted tumor growth in IFNAR(-/-) mice was retarded by adoptively transferring polyI:C-treated TICACM-1-positive mDCs but not TICAM-1(-/-) mDCs. Thus, TICAM-1 in mDCs critically facilitated mDC-NK contact and activation of antitumor NK, resulting in the regression of low MHC-expressing tumors.
authors.affiliation: Department of Immunology, Osaka Medical Center for Cancer, Nakamichi 1-3-2, Higashinari-ku, Osaka 537-8511, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Akazawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Ebihara
authors.forename: Manabu
authors.initials: M
authors.lastname: Okuno
authors.forename: Yu
authors.initials: Y
authors.lastname: Okuda
authors.forename: Masashi
authors.initials: M
authors.lastname: Shingai
authors.forename: Kunio
authors.initials: K
authors.lastname: Tsujimura
authors.forename: Toshitada
authors.initials: T
authors.lastname: Takahashi
authors.forename: Masahito
authors.initials: M
authors.lastname: Ikawa
authors.forename: Masaru
authors.initials: M
authors.lastname: Okabe
authors.forename: Norimitsu
authors.initials: N
authors.lastname: Inoue
authors.forename: Miki
authors.initials: M
authors.lastname: Okamoto-Tanaka
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Ishizaki
authors.forename: Jun
authors.initials: J
authors.lastname: Miyoshi
authors.forename: Misako
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Seya
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000502:physiology*; D000818:Animals; D003713:Dendritic Cells / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D008546:Melanoma, Experimental / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000276:immunology*; D011070:Poly I-C / Q000494:pharmacology; D053633:Receptor, Interferon alpha-beta / Q000502:physiology; D051196:Toll-Like Receptor 3 / Q000502:physiology*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D011070:Poly I-C; D053633:Receptor, Interferon alpha-beta; D051196:Toll-Like Receptor 3; C508032:Ifnar1 protein, mouse; C476286:Ticam1 protein, mouse