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

Abstract

Human papillomavirus (HPV) is an etiological risk factor for a subset of head and neck squamous cell carcinoma (HNSCC). HPV+ HNSCC is significant more radiosensitive than HPV-HNSCC, but the underlying mechanism is still unknown. Tumor microenvironment can affect tumor response to radiation therapy. Cancer secreted exosomes are emerging as crosstalk mediators between tumor cells and the tumor microenvironment. The main objectives of this study were to determine the role of HPV+ HNSCC-derived exosomes in increased radiation sensitivity. Here, we found that exosomes derived from HPV+ HNSCC cells activate macrophages into the M1 phenotype, which then increases the radiosensitivity of HNSCC cells. miR-9 was enriched in exosomes released from HPV+ HNSCC cells and it could be transported to macrophages, leading to altered cellular functions. Overexpression of miR-9 in macrophages induced polarization into the M1 phenotype via downregulation of PPARδ. Increased radiosensitivity was observed for HNSCC cells co-cultured with macrophages in which miR-9 was upregulated or treated with M1 macrophages. These observations suggest that HPV+ HNSCC cells secrete miR-9-rich exosomes, which then polarize macrophages into M1 phenotype and lead to increased radiosensitivity of HNSCC cells. Hence, miR-9 may be a potential treatment strategy for HNSCC..

The roles of extracellular vesicles in the development, microenvironment, anticancer drug resistance, and therapy of head and neck squamous cell carcinoma

“…Further evidence showed that thrombospondin 1 (THBS1) derived from OSCC EXOs is involved in the polarization of macrophages towards an M1-like phenotype and creates conditions that promote OSCC progression [114]. MiRNA-9-rich EXOs derived from HPV (+) HNSCC lead to polarization of macrophage M1 via downregulation of peroxisome proliferator-activated receptor δ (PPARδ) and increase the radiosensitivity of tumours [115]. Hence, miRNA-9 may be used as a potential treatment for HNSCC.…”

In-silico, interactomic and clinical validation based approach for screening and identification of miR biomarkers involved in Oral submucous fibrosis to Oral squamous cell carcinoma transition

“…Protein targeting plays key role in cancer signaling such as evading growth repressors, angiogenesis, and metastasis signaling therefore contribution of miR-9-5p contribution can’t be ignored. Also, there is a recent study which found miR-9 enriched in HPV infected HNSCC patients and downregulates PPARD to induce macrophage polarization[47]. miR-1 is enriched in ARP2/3 complex mediated actin nucleation and regulation of actin filament polymerization also in transport and localization.…”

The Emerging Role of Exosomes in Diagnosis, Prognosis, and Therapy in Head and Neck Cancer

“…The presence of CD47, a supposed antiphagocytic molecule, on HPV(+) TEX might support prolonged interactions with immune cells [49]. Recently, HPV(+) TEX were found to foster M1 polarization of macrophages via miR-9, which may contribute to radiosensitivity of HNSCC [50].…”