TLR-9介导口腔黏膜癌变细胞抑制pDC免疫监控功能的分子机制研究

It is well known that immune dysfunction has close relation with tumor occurrence and development. Our previous research identified elevated TLR-9 expression has close relation with immune dysfunction during the malignant transformation of oral mucosa epithelitis to squamous cell carcinoma, and TLR-9 is strongly suspected to be one of the key regulatory factors in tumor immune escape. However, little is known about the regulating mechanism in detail on TLR-9 mediated oral cancerous cell immune escape. By further literature review and preliminary experiment, we found that circulating pDCs in peripheral blood migrated to cancerous site during oral mucosa carcinogenesis, and tumor-infiltrating pDCs number has a positive correlation with TLR-9 expression. However, tumor-infiltrating pDCs in cancerous site showed a significant decreased immune function. Thus we speculate that oral cancerous cell could chemically attract circulating pDCs to cancerous site and inhibit its immune function via TLR-9 activation, which may play a key role in the initial stage of cancerous cell escaping from immune surveillance and control. Based on combined utilization of genoinformatics,molecular immunology,cytobiology and experimental zoology, the present study try to further explore the possible initial mechanisms in oral mucosa caicinogensis from immune regulatory level. We believe this research would provide new information and inspiration in prevention and treatment of immune dysfunction-related oral squamous cell carcinoma in the future.

免疫稳态失衡与恶性肿瘤的发生发展关系密切。课题组的前期研究明确了口腔粘膜上皮癌变过程中TLR-9的高表达与癌变微环境的免疫稳态失衡密切相关，极有可能是口腔黏膜癌变细胞免疫逃逸的关键调控节点之一。然而，对于癌变过程中TLR-9介导癌变细胞逃避机体免疫监控的具体机制仍未明确。结合文献检索及预初实验，课题组发现循环于外周血内的pDC细胞在口腔黏膜上皮癌变过程中特异性的迁徙至癌变部位，其聚集水平与癌变细胞TLR-9的表达水平明显正相关，但免疫功能状态却显著降低。由此，课题组推测“TLR-9介导癌变细胞趋化外周血pDC至癌变发生部位并抑制其免疫监控功能可能是口腔癌变细胞逃避机体免疫识别与清除的关键初始环节”，并希望综合运用基因信息学、分子免疫学、细胞生物学及实验动物学等学科交叉的研究方式，从免疫调控角度对口腔黏膜上皮癌变的始发机制进行深入研究，为口腔鳞癌免疫相关发病机制的探索提供新的启示。

免疫稳态失衡与恶性肿瘤的发生发展关系密切。课题组的前期研究明确了口腔粘膜上皮癌变过程中TLR-9的高表达与癌变微环境的免疫稳态失衡密切相关，极有可能是口腔黏膜癌变细胞免疫逃逸的关键调控节点之一。然而，对于癌变过程中TLR-9介导癌变细胞逃避机体免疫监控的具体机制仍未明确。首先，本项目明确了口腔上皮癌变过程中存在pDC细胞显著增高的组织浸润，浸润的pDC细胞在数量上与癌变进程明显相关，但在功能上却明显下降；其次而且癌变组织内浸润的pDC与TLR-9的过表达明显相关，TLR-9的过表达可显著降低浸润的pDC分泌IFNα的能力；随后课题组进一步证明TLR-9可通过介导口腔癌变细胞抑制pDC细胞的免疫监控功能，且至少部分是通过TGF-β和IL-10实现的；进一步地，探索过程中意外的发现TNF-α/NF-κB/CXCR-4通路在肿瘤浸润pDC促进口腔鳞癌增殖及淋巴结转移中发挥了重要的作用；本课题的顺利实施势必会在口腔癌免疫治疗及口腔鳞状细胞癌癌变及转移机制的探讨中发挥重要的作用。通过本项目的开展实施，课题组培养了1名硕士研究生毕业，培养了口腔肿瘤实验室技术骨干1名，使得本课题组在肿瘤的免疫治疗的研究上提高了一个水平，并能够以此基础，开展下一步的深入研究。并在前期研究基础的份上，成功申请并中标国家自然科学基金面上项目1项（Grant NO. 82072983），截止2021年12月，已经发表课题相关SCI论文4篇（IF>5 分1篇；IF>3分1篇），均标注国家自然自然科学基金资助（Grant NO. 81772870）。