M2 macrophages reduce the radiosensitivity of head and neck cancer by releasing HB-EGF

The aim of the present study was to examine the potential role of human heparin-binding epidermal growth factor (HB-EGF) secreted by M2 macrophages in the development of radioresistance in head and neck squamous cell carcinoma (HNSCC). Immunohistochemistry was used to detect radiosensitivity in human papilloma virus (HPV)-positive and HPV-negative HNSCC tissues and immunohistochemical staining with specific antibodies for macrophage surface markers was used to assess the infiltration of M1 and M2 macrophages in HPV-positive and -negative HNSCC tissues. The expression of HB-EGF in HPV-positive and -negative HNSCC tissues was determined by multi-cytokine detection in order to determine the relationship between HB-EGF and radiosensitivity. M1 and M2 macrophages were co-cultured with the HNSCC cell line CAL27 and treated with HB-EGF and its neutralizing antibodies to assess radiation sensitivity. Finally, the major DNA double-strand break repair pathways required for the activation of HB-EGF and promotion of epidermal growth factor receptor (EGFR) were identified. The results revealed that radiosensitivity was higher in HPV-positive HNSCC compared with HPV-negative. There was a higher infiltration of M2 macrophages in HPV-negative HNSCC, which were revealed as the main source of HB-EGF secretion. Furthermore, it was determined that overexpression of HB-EGF induced radioresistance in HPV-negative HNSCC. HB-EGF promoted the activation of the non-homologous end-joining pathway by activating EGFR. To the best of our knowledge, this is the first study to demonstrate the association between HB-EGF and radiosensitivity in HNSCC. These results indicated that the secretion of HB-EGF by M2 macrophages could induce radioresistance of HPV-negative HNSCC.