title: Toll-like receptor 3 regulates NK cell responses to cytokines and controls experimental metastasis.
abstract: The Toll-like receptor 3 (TLR3) agonist poly(I:C) is a promising adjuvant for cancer vaccines due to its induction of potent antitumor responses occurring primarily through the activation of dendritic cells (DCs) and natural killer (NK) cells. However, little is known about the role of TLR3 sensing of endogenous ligands in innate tumor immunosurveillance. Here, we investigated whether TLR3 could modulate immune responses and facilitate tumor control without administration of an agonist. We observed only limited impact of TLR3 deficiency on spontaneous carcinogenesis and primary growth of B16F10, E0771 or MC38 tumors when injected subcutaneously to mice. Nevertheless, TLR3 was observed to limit experimental B16F10 lung metastasis, an immunologic constraint dependent on both IFNγ secretion and NK cells. Interestingly, we observed that NK cells derived fromTlr3null (Tlr3-/-) mice were hyporesponsive to cytokine stimulation. Indeed, compared with NK cells with intact TLR3,Tlr3-/-NK cells produced significantly reduced pro-inflammatory cytokines, including IFNγ, when incubated in the presence of different combinations of IL-12, IL-18 and IL-15. Bone-marrow chimera experiments established that competent NK cell responses required TLR3 sensing on radio-sensitive immune cells. Intriguingly, although CD8α DCs robustly express high levels of TLR3, we found that those cells were not necessary for efficient IFNγ production by NK cells. Moreover, the defective NK cell phenotype ofTlr3-/-mice appeared to be independent of the gut microbiota. Altogether, our data demonstrate a pivotal role of endogenous TLR3 stimulation for the acquisition of full NK cell functions and immune protection against experimental metastasis.
authors.affiliation: Immunology of Cancer and Infection Laboratory; QIMR Berghofer Medical Research Institute ; Herston, Queensland, Australia ; School of Medicine; University of Queensland ; Herston, Queensland, Australia.
authors.forename: Camille
authors.initials: C
authors.lastname: Guillerey
authors.affiliation: Immunology of Cancer and Infection Laboratory; QIMR Berghofer Medical Research Institute ; Herston, Queensland, Australia.
authors.forename: Melvyn T
authors.initials: MT
authors.lastname: Chow
authors.affiliation: Immunology of Cancer and Infection Laboratory; QIMR Berghofer Medical Research Institute ; Herston, Queensland, Australia.
authors.forename: Kim
authors.initials: K
authors.lastname: Miles
authors.affiliation: Bone Marrow Transplantation; QIMR Berghofer Medical Research Institute ; Herston, Queensland, Australia.
authors.forename: Stuart
authors.initials: S
authors.lastname: Olver
authors.affiliation: Tumour Microenvironment Laboratory; QIMR Berghofer Medical Research Institute ; Herston, Queensland, Australia.
authors.forename: Jaclyn
authors.initials: J
authors.lastname: Sceneay
authors.affiliation: Department of Immunology; Juntendo University School of Medicine ; Hongo, Tokyo, Japan.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Takeda
authors.affiliation: School of Medicine; University of Queensland ; Herston, Queensland, Australia ; Tumour Microenvironment Laboratory; QIMR Berghofer Medical Research Institute ; Herston, Queensland, Australia.
authors.forename: Andreas
authors.initials: A
authors.lastname: Möller
authors.affiliation: Immunology of Cancer and Infection Laboratory; QIMR Berghofer Medical Research Institute ; Herston, Queensland, Australia ; School of Medicine; University of Queensland ; Herston, Queensland, Australia.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
keywords: NK cell; TLR; cytokine; metastasis; mouse