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.

中文翻译：

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HPV + HNSCC衍生的外泌体miR-9诱导巨噬细胞M1极化并增加肿瘤放射敏感性。

人乳头瘤病毒（HPV）是一部分头颈部鳞状细胞癌（HNSCC）的病因危险因素。HPV + HNSCC对辐射的敏感性比HPV-HNSCC高，但是，这种观察所依据的机制仍然未知。肿瘤微环境可以调节肿瘤对放射治疗的反应。分泌性外来体正在作为肿瘤细胞与肿瘤微环境之间的串扰介体而出现。在这项研究中，我们试图确定HPV + HNSCC外泌体在增加放射敏感性中的作用。我们发现HPV + HNSCC外泌体能够将巨噬细胞转化为M1表型，从而增加了HNSCC的放射敏感性。发现miR-9富含HPV + HNSCC外泌体，可以转运至巨噬细胞，通过下调PPARδ诱导M1巨噬细胞极化。与M1巨噬细胞或经miR-9模拟物处理的巨噬细胞孵育后，HNSCC的放射敏感性显着提高。通过使用来自The Cancer Genome Atlas的分析数据，证实了miR-9在HNSCC中的临床意义。我们的数据表明，来自HPV + HNSCC的富含miR-9的外泌体可以使巨噬细胞极化为M1表型，并增加HPV + HNSCC的放射敏感性。因此，miR-9可用作HNSCC的潜在治疗方法。