M2 macrophages reduce the radiosensitivity of head and neck cancer by releasing HB­EGF.

The aim of the present study was to examine the potential role of human heparin­binding epidermal growth factor (HB­EGF) 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 HPV­negative HNSCC tissues and immunohistochemical staining with specific antibodies for macrophage surface markers was used to assess the infiltration of M1 and M2 macrophages in HPV­positive and ­negative HNSCC tissues. The expression of HB­EGF in HPV­positive and ­negative HNSCC tissues was determined by multi­cytokine detection in order to determine the relationship between HB­EGF and radiosensitivity. M1 and M2 macrophages were co­cultured with the HNSCC cell line CAL27 and treated with HB­EGF and its neutralizing antibodies to assess radiation sensitivity. Finally, the major DNA double­strand break repair pathways required for the activation of HB­EGF and promotion of epidermal growth factor receptor (EGFR) were identified. The results revealed that radiosensitivity was higher in HPV­positive HNSCC compared with HPV­negative. There was a higher infiltration of M2 macrophages in HPV­negative HNSCC, which were revealed as the main source of HB­EGF secretion. Furthermore, it was determined that overexpression of HB­EGF induced radioresistance in HPV­negative HNSCC. HB­EGF promoted the activation of the non­homologous end­joining pathway by activating EGFR. To the best of our knowledge, this is the first study to demonstrate the association between HB­EGF and radiosensitivity in HNSCC. These results indicated that the secretion of HB­EGF by M2 macrophages could induce radioresistance of HPV­negative HNSCC.

IL-6 induced M1 type macrophage polarization increases radiosensitivity in HPV positive head and neck cancer.

Radiation is a crucial component of head and neck squamous cell carcinoma (HNSC) treatment. Human papillomavirus-positive (HPV+) HNSC is significantly more radiosensitive than HPV- HNSC, but the mechanism underlying this increased sensitivity is unknown. We investigated the possible involvement of macrophage subpopulations as key mediators of HNSC radiosensitivity linked to HPV status. We collected forty-one clinical HNSC specimens and determined HPV status and radiosensitivity of each sample. We investigated cytokine mediated induction of macrophage polarization by HPV+ and HPV- HNSC cells. Radiosensitive HNSC tissues exhibited greater numbers of infiltrating M1 macrophages than radioresistant tumor tissue samples. Moreover, M1 macrophage numbers were positively correlated with HNSC radiosensitivity. HPV+ and HPV- tumor cells induced macrophage polarization to M1 and M2 type, respectively. HPV+ HNSC cells secreted more IL-6 than HPV- cells. HPV promoted tumor cell secretion of IL-6, thereby increasing radiosensitivity through M1 polarization of macrophages. M1 macrophages represent an important tissue microenvironment factor with implications for HNSC treatment efficacy and may prove valuable as a biomarker of radiation sensitivity.

Association of lnc-IL17RA-11 with increased radiation sensitivity and improved prognosis of HPV-positive HNSCC.

Human papillomavirus (HPV) associated head and neck squamous cell carcinoma (HNSCC) has a far better prognosis than HPV negative HNSCC. Recent studies suggest that long noncoding RNA (lncRNA) moieties may play a role in HPV associated differential HNSCC prognoses. In this study, we examined differential expression of lncRNAs in HPV+ vs HPV- HNSCC using The Cancer Genome Atlas database. LncRNAs were categorized based on expression level and survival analysis. A group of eight lncRNAs was identified in which altered expression was associated with both HPV infection and better prognosis. Subsequently, genes coexpressed with these lncRNAs in HNSCC cells were sorted into corresponding co-expression modules. The lnc-IL17RA-11 coexpression module exhibited the greatest correlation with HPV infection and radiotherapy efficacy. We identified the lnc-IL17RA-11 transcription factor ER-alpha as the most likely HPV infection associated factor promoting increased lnc-IL17RA-11 levels. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis revealed enrichment among lnc-IL17RA-11 co-expressed genes for functions related to DNA replication and cell proliferation. These observations are consistent with a model in which HPV infection upregulates transcription factor ER-alpha, which increases levels of lnc-IL17RA-11 and coexpressed genes that promote HNSCC cell sensitivity to radiotherapy, thereby improving disease prognosis.