Toll-like receptor 3 regulates NK cell responses to cytokines and controls experimental metastasis

Guillerey, Camille, Chow, Melvyn T., Miles, Kim, Olver, Stuart, Sceneay, Jaclyn, Takeda, Kazuyoshi, Möller, Andreas and Smyth, Mark J. (2015) Toll-like receptor 3 regulates NK cell responses to cytokines and controls experimental metastasis. Oncoimmunology, 4 9: 1-11. doi:10.1080/2162402X.2015.1027468

Author Guillerey, Camille
Chow, Melvyn T.
Miles, Kim
Olver, Stuart
Sceneay, Jaclyn
Takeda, Kazuyoshi
Möller, Andreas
Smyth, Mark J.
Title Toll-like receptor 3 regulates NK cell responses to cytokines and controls experimental metastasis
Journal name Oncoimmunology   Check publisher's open access policy
ISSN 2162-402X
Publication date 2015
Sub-type Article (original research)
DOI 10.1080/2162402X.2015.1027468
Open Access Status Not Open Access
Volume 4
Issue 9
Start page 1
End page 11
Total pages 11
Place of publication New York, NY, United States
Publisher Taylor & Francis
Collection year 2016
Language eng
Formatted 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 from Tlr3 null (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 of Tlr3−/− 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.
Keyword NK cell
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
School of Medicine Publications
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