Natural killer (NK) cells play a dominant role in the network of innate immunity. Via Toll-like receptor 3 (TLR3), NK cells can be efficiently stimulated by double-stranded (ds)RNA. In head and neck squamous cell carcinoma (HNSCC), NK cells seem to be strongly impaired, but the true mechanisms of immune escape are not sufficiently known to date. It is obvious that the microenvironment of head and neck cancer results in strongly affected immune functions. NK cells play a major role in the local immune response of HNSCC. In this study we showed that TLR3 is predominantly expressed on the cell surface of native NK cells and becomes rapidly internalized in response to the HNSCC microenvironment. These findings represent a novel potential immune escape mechanism of head and neck cancer. The internalization of TLR3 in response to HNSCC was also observed in fibroblasts expressing heterologous TLR3 protein. Specific stimulation of NK cell TLR3 with its ligand polyinosinic-polycytidylic acid (Poly I:C) impairs the internalization of this Toll-like receptor and leads to activated NK cells within the HNSCC microenvironment.

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