PDF(Pubmed)
Abstract：
Head and neck squamous cell carcinoma (HNSCC) is a global cancer burden with a 5-year overall survival rate of around 50%, stagnant for decades. A tumour-induced immunosuppressive microenvironment contributes to HNSCC progression, with the adenosine (ADO) pathway and an upregulated expression of inhibitory immune checkpoint regulators playing a key role in this context. The correlation between high neutrophil-to-lymphocyte ratio (NLR) with advanced tumour staging suggests involvement of neutrophils (NØ) in cancer progression. Interestingly, we associated a high NLR with an increased intracellular PD-L1 localization in primary HNSCC samples, potentially mediating more aggressive tumour characteristics and therefore synergistically favouring tumour progression. Still, further research is needed to harness this knowledge for effective treatments and overcome resistance. Since it is hypothesized that the tumour microenvironment (TME) may be influenced by small extracellular vesicles (sEVs) secreted by tumours (TEX), this study aims to investigate the impact of HNSCC-derived TEX on NØ and blockade of ADO receptors as a potential strategy to reverse the pro-tumour phenotype of NØ. UMSCC47-TEX exhibited CD73 enzymatic activity involved in ADO signalling, as well as the immune checkpoint inhibitor PD-L1. Data revealed that TEX induce chemotaxis of NØ and the sustained interaction promotes a shift into a pro-tumour phenotype, dependent on ADO receptors (P1R), increasing CD170high subpopulation, CD73 and PD-L1 expression, followed by an immunosuppressive secretome. Blocking A3R reduced CD73 and PD-L1 expression. Co-culture experiments with HNSCC cells demonstrated that TEX-modulated NØ increase the CD73/PD-L1 axis, through Cyclin D-CDK4/6 signalling. To support these findings, the CAM model with primary tumour was treated with NØ supernatant. Moreover, these NØ promoted an increase in migration, invasion, and reduced cell death. Targeting P1R on NØ, particularly A3R, exhibited potential therapeutic strategy to counteract immunosuppression in HNSCC. Understanding the TEX-mediated crosstalk between tumours and NØ offers insights into immunomodulation for improving cancer therapies.
摘要：
头颈部鳞状细胞癌（HNSCC）是全球癌症负担，5年总生存率约为50％。停滞了几十年。肿瘤诱导的免疫抑制微环境有助于HNSCC进展，腺苷（ADO）途径和抑制性免疫检查点调节因子的上调表达在这方面起关键作用。高中性粒细胞与淋巴细胞比率（NLR）与晚期肿瘤分期之间的相关性表明中性粒细胞（NØ）参与了癌症进展。有趣的是,我们将高NLR与原代HNSCC样品中细胞内PD-L1定位增加相关联，可能介导更具侵袭性的肿瘤特征，因此协同促进肿瘤进展。尽管如此，需要进一步的研究来利用这些知识进行有效的治疗并克服耐药性。由于假设肿瘤微环境（TME）可能受到肿瘤（TEX）分泌的小细胞外囊泡（sEV）的影响，这项研究旨在研究HNSCC衍生的TEX对NØ的影响以及阻断ADO受体作为逆转NØ肿瘤前表型的潜在策略。UMSCC47-TEX表现出参与ADO信号传导的CD73酶活性，以及免疫检查点抑制剂PD-L1。数据显示，TEX诱导NØ的趋化性，持续的相互作用促进了向肿瘤前表型的转变，依赖ADO受体（P1R），增加CD170high亚群，CD73和PD-L1表达，其次是一个免疫抑制的分泌体。阻断A3R降低CD73和PD-L1表达。与HNSCC细胞的共培养实验表明，TEX调节的NO可增加CD73/PD-L1轴，通过细胞周期蛋白D-CDK4/6信号传导。为了支持这些发现，具有原发性肿瘤的CAM模型用N.0上清液处理。此外，这些NØ促进了移民的增加，入侵,减少细胞死亡。瞄准NØ上的P1R,尤其是A3R,表现出潜在的治疗策略来对抗HNSCC的免疫抑制。了解TEX介导的肿瘤和NØ之间的串扰提供了对免疫调节改善癌症治疗的见解。
