口腔鳞癌严重威胁患者健康及生存质量，其恶性进展过程与肿瘤微环境中免疫逃逸的发生密切相关，其中肿瘤相关成纤维细胞（CAFs）起到了重要的调控作用。申请者前期研究发现:①经CAFs处理后口腔鳞癌细胞对NK的杀伤产生了明显抵抗，并且这一效应与肿瘤细胞表面抑制性NK配体HLA-E的上调相关；②CAFs发挥免疫抑制效应与其释放的细胞因子TNFα及肿瘤细胞内NF-κB信号通路的激活相关。据此我们提出假说：在口腔鳞癌微环境中，CAFs通过释放TNFα激活肿瘤细胞内NF-κB信号通路，上调肿瘤细胞HLA-E的表达造成肿瘤细胞的NK杀伤逃逸。本项目聚焦肿瘤微环境中免疫逃逸现象，探讨CAFs-TNFα/NF-κB/HLA-E轴在促进NK杀伤抵抗方面的作用和机制；进一步通过对口腔鳞癌临床样本分析及小鼠模型研究，为口腔鳞癌患者预后判断提供参考，并重点评估HLA-E单抗在口腔鳞癌免疫治疗中的价值。

Oral squamous cell carcinoma (OSCC) severely affected the survival and living quality of patients. The malignant development of OSCC is associated with the evasion from immunosurveillance in the tumor microenvironment (TME). Besides, cancer associated fibroblasts (CAFs) play crucial part in this progression. Our previous researches showed that after the co-culture with CAFs or treatment with conditional medium (CM) of CAFs, OSCC raised significant resistance to NK cytotoxicity. The effect was related to the enhanced expression of HLA-E, the inhibitory ligand to NK. Moreover, the cytokine TNFα secreted by CAFs was involved, which activated NF-κB signaling pathway in OSCC cells. According to our previous studies, we speculate that CAFs-secreted TNFα might increase HLA-E expression of tumor cells through the activation of NF-κB signaling pathway, which promotes immune escape in the TME of OSCC. In this study, we mainly focus on the immunomodulatory mechanism of the CAFs-TNFα/NF-κB/HLA-E axis. The feasibility of HLA-E as a potential prognostic marker and therapeutic target for OSCCs will be evaluated by further studies in OSCC samples and the xenograft models in immunodeficient mice. Furthermore, we will emphasize on the value assessment of anti-HLA-E monoclonal antibody in immunotherapy of OSCC in the future.