TLR-4 regulates neutrophil trafficking and tumor progression in HNSCC

Introduction:

Neutrophils have been implicated in induction, progression, and metastasis of malignant tumors including head and neck squamous cell carcinoma (HNSCC). How these immune cells reach these neoplastic lesions, however, is poorly understood. Toll-like receptor-4 (TLR-4) is a transmembrane receptor that induces immune responses upon recognizing damage-associated or pathogen-associated molecular patterns (DAMPs/PAMPs). The role of this receptor in HNSCC, however, remains largely obscure.

Methods:

Effects of DAMPs on immune cell trafficking were first screened in a mouse peritonitis assay. Subsequently, neutrophil responses as well as tumor growth in experimental mouse HNSCC (cell line SCC VII) were analyzed by multi-channel flow cytometry (orthotopic model in floor of mouth) or in vivo microscopy (heterotopic model in auricula).

Results:

Tumor-released DAMP S100A8/A9, but not high-mobility group box 1 (HMGB1) induced neutrophil recruitment to the peritoneal cavity. This effect of S100A8/A9 was dependent on its receptor TLR-4, but not on its alternative interaction partner receptor for advanced glycosylation endproducts (RAGE). Conversely, blockade of TLR-4 significantly reduced neutrophil infiltration of HNSCC as well as responses of these immune cells in the peritumoral microvasculature. As a consequence of these events, tumor growth was significantly attenuated upon TLR-4 blockade.

Conclusions:

TLR-4 critically regulates neutrophil trafficking and tumor progression in experimental HNSCC. Consequently, this pattern recognition receptor might emerge as promising therapeutic target in head and neck immuno-oncology.

Publication History

Publication Date:
23 April 2019 (online)