HPV16 E2 induced M1 macrophage polarization in head and neck cancer microenvironment by exosomal miR-619-5p

The sensitivity of HPV-positive (HPV+) head and neck squamous cell carcinoma (HNSC) to radiotherapy and chemotherapy is higher than that of HPV-negative (HPV-) HNSC, a phenomenon that is associated with its pro-inflammatory immune microenvironment. Previous studies have demonstrated that HPV can induce macrophages to polarize towards the M1 type in HNSC microenvironment. However, the precise mechanisms underlying the increased infiltration of M1 type macrophages remains unclear. In this study, we explored the role of exosomes in the M1 macrophage polarization in HNSC linked to the HPV E2. Our bioinformatics analysis revealed that HNSC with highly expression of HPV E2 is characterized by enhanced infiltration of M1 macrophages. Exosomes derived from HNSC cells overexpressing HPV E2 (HPV E2+) induce macrophage polarization towards the M1 type. Specifically, we discovered that miR-619-5p, which is significantly reduced in HPV E2+ HNSC exosomes, promotes the polarization of macrophages to the M2 type by inhibiting VAV3. This reduction in exosomal miR-619-5p is a key factor in the M1 macrophage polarization seen in HPV E2+ HNSC. Consequently, miR-619-5p could serve as a potential therapeutic target and a candidate biomarker for predicting the pro-inflammatory microenvironment in HNSC.