High-risk human papillomavirus (HPV) infection is one of the leading causes of oropharyngeal squamous cell carcinoma (OPSCC), while the correlation between HPV and oral squamous cell carcinoma (OSCC) remains controversial. The inflammatory infiltrate involved in these epithelial neoplasms differs based on their association with HPV. HPV− tumors show higher tumor-associated neutrophil (TAN) infiltration. It is believed that TANs can play a dual role in cancer by exerting either anti-tumorigenic or pro-tumorigenic effects. However, the impact of HPV status on neutrophil polarization remains unknown. Therefore, this study aimed to investigate the effect of OSCC cells, both HPV− and HPV16+, on the functional phenotype of neutrophils. Peripheral blood neutrophils were stimulated with supernatants from OSCC cell lines and non-tumorigenic HaCaT keratinocytes transduced with HPV16 E6/E7 oncogenes. Subsequently, cytokine production, cell viability, metabolism, expression of degranulation markers, and PD-L1 expression were evaluated. Our findings demonstrate that in contrast to UPCI:SCC154 (HPV+ OSCC) cells, the SCC-9 (HPV− OSCC) cell line induced a highly activated functional state in neutrophils, which is potentially associated with a pro-tumorigenic effect. The HaCaT 16-E7 supernatant only stimulated the activation of some neutrophil functions. Understanding the complex interplay between neutrophils and their microenvironment has the potential to identify TANs as viable therapeutic targets.
高危型人乳头瘤病毒（HPV）感染是口咽鳞状细胞癌（OPSCC）的主要致病因素之一，而HPV与口腔鳞状细胞癌（OSCC）之间的关联仍存争议。这些上皮性肿瘤所涉及的炎症浸润因其与HPV的相关性而存在差异。HPV阴性肿瘤表现出更高的肿瘤相关中性粒细胞（TAN）浸润。目前认为TAN在癌症中可通过发挥抗肿瘤或促肿瘤效应扮演双重角色。然而，HPV状态对中性粒细胞极化的影响尚不明确。因此，本研究旨在探讨HPV阴性及HPV16阳性OSCC细胞对中性粒细胞功能表型的影响。通过使用OSCC细胞系及转导HPV16 E6/E7癌基因的非致瘤性HaCaT角质形成细胞的上清液刺激外周血中性粒细胞，进而评估细胞因子产生、细胞活力、代谢、脱颗粒标志物表达及PD-L1表达水平。研究结果显示，与UPCI:SCC154（HPV阳性OSCC）细胞相比，SCC-9（HPV阴性OSCC）细胞系能诱导中性粒细胞进入高度活化的功能状态，该状态可能与促肿瘤效应相关。而HaCaT 16-E7细胞上清仅能刺激部分中性粒细胞功能的活化。理解中性粒细胞与其微环境之间复杂的相互作用，有望将TAN确立为可行的治疗靶点。
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