Molecular and Translational Immunology Laboratory, Clinical Biochemistry and Immunology Department, Pharmacy Faculty, Universidad de Concepción, Concepción, Chile.
Anatomy Pathology Unit and Dental Service, Oral Pathology Department, Hospital Las Higueras, Talcahuano, Chile.
Front Immunol. 2021 May 7;12:643298. doi: 10.3389/fimmu.2021.643298. eCollection 2021.
The immune system plays a key role in the protective response against oral cancer; however, the tumor microenvironment (TME) impairs this anti-cancer response by modulating T helper (Th) responses and promoting an anti-inflammatory environment. Regulatory T cells (Tregs) and Th2 effector cells (Teff) are associated with poor prognosis in oral squamous cell carcinoma (OSCC). However, the main immunomodulatory mechanisms associated with the enrichment of these subsets in OSCC remain unknown. We characterized Th-like lineages in Tregs and Teff and evaluated immunomodulatory changes induced by the TME in OSCC. Our phenotypic data revealed a higher distribution of tumour-infiltrating CCR8 and Th2-like Treg in OSCC compared with non-malignant samples, whereas the percentages of Th1 cells were reduced in cancer. We then analyzed the direct effect of the TME by exposing T cell subsets to cancer secretomes and observed the OSCC secretome induced CCR8 expression and reduced cytokine production from both subsets. Transcriptomic analysis showed that the co-culture with OSCC secretome induced several gene changes associated with the vitamin D (VitD) signaling pathway in T cells. In addition, proteomic analysis identified the presence of several proteins associated with prostaglandin E2 (PGE2) production by rapid membrane VitD signaling and a reduced presence of the VitD binding protein. Thus, we analyzed the effect of VitD and PGE2 and observed that VitD promotes a regulatory Th2-like response with CCR8 expression whilst PGE2 also modulated CCR8 but inhibited cytokine production in combination with VitD. Finally, we evaluated the presence of CCR8 ligand in OSCC and observed increased chemokine CCL18, which was also able to upregulate CCR8 in activated Th cells. Overall, our data showed the immunomodulatory changes induced by the TME involving CCR8 expression and regulatory Th2 phenotypes, which are associated with PGE2 mediated VitD signaling pathway and CCL18 expression in OSCC.
免疫系统在对抗口腔癌的保护反应中发挥着关键作用；然而，肿瘤微环境（TME）通过调节辅助性 T 细胞（Th）反应并促进抗炎环境来损害这种抗癌反应。调节性 T 细胞（Tregs）和 Th2 效应细胞（Teff）与口腔鳞状细胞癌（OSCC）的预后不良相关。然而，与这些亚群在 OSCC 中富集相关的主要免疫调节机制仍不清楚。我们对 Tregs 和 Teff 中的 Th 样谱系进行了表征，并评估了 TME 对 OSCC 中免疫调节的变化。我们的表型数据显示，与非恶性样本相比，OSCC 中肿瘤浸润性 CCR8 和 Th2 样 Treg 的分布更高，而癌症中 Th1 细胞的比例降低。然后，我们通过将 T 细胞亚群暴露于癌症分泌组来分析 TME 的直接影响，并观察到 OSCC 分泌组诱导 CCR8 表达，并减少了两个亚群的细胞因子产生。转录组分析表明，与 OSCC 分泌组共培养诱导了 T 细胞中与维生素 D（VitD）信号通路相关的几个基因变化。此外，蛋白质组分析鉴定出了几种与快速膜 VitD 信号诱导的前列腺素 E2（PGE2）产生以及 VitD 结合蛋白的减少有关的蛋白质的存在。因此，我们分析了 VitD 和 PGE2 的作用，并观察到 VitD 促进具有 CCR8 表达的调节性 Th2 样反应，而 PGE2 也调节 CCR8，但与 VitD 联合抑制细胞因子产生。最后，我们评估了 OSCC 中 CCR8 配体的存在，并观察到趋化因子 CCL18 的增加，CCL18 也能够在上调激活的 Th 细胞中的 CCR8。总体而言，我们的数据显示了 TME 诱导的免疫调节变化，涉及 CCR8 表达和调节性 Th2 表型，这些变化与 OSCC 中的 PGE2 介导的 VitD 信号通路和 CCL18 表达有关。
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