HPV + HNSCC-derived exosomal miR-9 induces macrophage M1 polarization and increases tumor radiosensitivity

Human papillomavirus (HPV) is an etiological risk factor for a subset of head and neck squamous cell carcinoma (HNSCC). HPV + HNSCC is more radiosensitive than HPV- HNSCC, however, the mechanism underlying this observation remains unknown. Tumor microenvironment can regulate tumor response to radiation therapy. Secretory exosomes are emerging as crosstalk mediators between tumor cells and the tumor microenvironment. In this study, we attempted to determine the role of HPV + HNSCC exosomes in increased radiation sensitivity. We found that HPV + HNSCC exosomes were able to transform macrophages into the M1 phenotype, which subsequently increased the radiosensitivity of HNSCC. miR-9 was found enriched in HPV + HNSCC exosomes and it could be transported into macrophages, inducing M1 macrophage polarization via downregulation of PPARδ. After incubating with M1 macrophages or macrophages treated with miR-9 mimics, HNSCC had strikingly increased radiosensitivity. The clinical significance of miR-9 in HNSCC was confirmed by using profiling data from The Cancer Genome Atlas. Our data suggest that miR-9-enriched exosomes from HPV + HNSCC can polarize macrophages into M1 phenotype and increase the radiosensitivity of HPV + HNSCC. Hence, miR-9 may be used as a potential treatment for HNSCC.