Ghita Ioana, Piperi Evangelia, Atamas Sergei P, Bentzen Soren M, Ord Robert A, Dyalram Donita, Lubek Joshua E, Younis Rania H
Department of Oncology and Diagnostic Sciences, Division of Oral and Maxillofacial Pathology, University of Maryland School of Dentistry, Baltimore, MD, United States.
Department of Oral Medicine / Pathology and Hospital Dentistry, School of Dentistry, National and Kapodistrian University of Athens, Athens, Greece.
Front Oral Health. 2022 Sep 12;3:993638. doi: 10.3389/froh.2022.993638. eCollection 2022.
Head and neck squamous cell carcinoma (HNSCC) can be classified according to the histological inflammatory subtype (HIS) into inflamed (HIS-INF) or immune excluded (HIS-IE). HIS-IE was previously associated with higher levels of soluble Semaphorin 4D (HsS4D) in plasma, and higher transcriptional levels of osteopontin (OPN) in the tumor tissue, compared to HIS-INF. The goal of the current study is to investigate whether the HIS inflammatory subtype can be distinguished by a differential cytokine panel in peripheral blood. Retrospectively collected five HIS-INF and five HIS-IE tumor tissue with paired plasma were included in the study. Five healthy donors (HD) and five autoimmune/chronic inflammatory conditions (AI/CI) were controls. The ELISA-Luminex™ system was used to detect 40 traditional cytokines in plasma. Human cytokine array (104 cytokines) was used for the conditioned medium (CM) of the HNSCC HN6 cell line. Semaphorin 4D (Sema4D) siRNA and recombinant human osteopontin (rh-OPN) were used to investigate the effect of OPN on Sema4D expression. The HIS-IE cytokine profile was higher than HIS-INF but comparable to AI/CI. HIS-INF had the lowest cytokine levels. HIS-IE was differentially higher in IP-10 and IL8 compared to HD, while HIS-INF was higher in IL-10. Sema4D inhibition in HN6 resulted in a decrease of OPN in the CM of HN6, and treatment with rh-OPN rescued Sema4D in HN6 cell lysate and associated CM. In conclusion, the current work demonstrates a novel association between the HIS subtypes and a differential pattern of cytokine expression in plasma. These findings can open new avenues for HNSCC patient stratification and hence provide better personalized treatment.
头颈部鳞状细胞癌（HNSCC）可根据组织学炎症亚型（HIS）分为炎症型（HIS-INF）或免疫排除型（HIS-IE）。与HIS-INF相比，HIS-IE先前与血浆中可溶性信号素4D（HsS4D）水平较高以及肿瘤组织中骨桥蛋白（OPN）转录水平较高有关。本研究的目的是调查外周血中不同的细胞因子组是否可区分HIS炎症亚型。本研究纳入了回顾性收集的5例HIS-INF和5例HIS-IE肿瘤组织及配对血浆。5名健康供者（HD）和5例自身免疫/慢性炎症性疾病（AI/CI）作为对照。采用ELISA-Luminex™系统检测血浆中的40种传统细胞因子。用人细胞因子阵列（104种细胞因子）检测HNSCC HN6细胞系的条件培养基（CM）。使用信号素4D（Sema4D）小干扰RNA和重组人骨桥蛋白（rh-OPN）研究OPN对Sema4D表达的影响。HIS-IE细胞因子谱高于HIS-INF，但与AI/CI相当。HIS-INF的细胞因子水平最低。与HD相比，HIS-IE的IP-10和IL-8水平差异更高，而HIS-INF的IL-10水平更高。对HN6中的Sema4D进行抑制导致HN6的CM中OPN减少，用rh-OPN处理可挽救HN6细胞裂解物及相关CM中的Sema4D。总之，目前的研究表明HIS亚型与血浆中细胞因子表达的差异模式之间存在新的关联。这些发现可为HNSCC患者分层开辟新途径，从而提供更好的个性化治疗。
