ENPP1通过cGAS-STING和腺苷信号通路调控头颈鳞癌免疫抑制的作用机制研究

头颈鳞癌是常见的恶性肿瘤之一，复发/转移性头颈鳞癌患者生存率不足一年。免疫检查点抑制剂已在复发/转移性头颈鳞癌治疗中显示出明显优势，但其问题在于总体应答率不足20%，头颈鳞癌免疫治疗的有效率亟待提高。本研究首次发现ENPP1在头颈鳞癌中异常高表达，与此同时CD8+T细胞表达减少；细胞实验发现ENPP1能够水解胞外cGAMP。ENPP1作为胞外酶，其底物cGAMP和水解产物腺苷均在肿瘤免疫调节中起重要作用。因此我们假设ENPP1是调控头颈鳞癌免疫的重要分子，靶向抑制ENPP1可能成为头颈鳞癌免疫治疗的新靶点。本课题拟利用头颈上皮特异性ENPP1基因敲除小鼠以及体外实验探究ENPP1调控cGAS-STING和腺苷通路在头颈鳞癌免疫抑制中的作用及机制，并研究ENPP1抑制剂单独或联合PD-L1单抗用于免疫治疗的效果，为提高头颈鳞癌免疫治疗有效率提供新靶点和新策略。

Head and neck squamous cell carcinoma is one of the most common cancers, the survival rate of patients with recurrent / metastatic head and neck squamous cell carcinoma is less than one year. Immune checkpoint inhibitors have shown obvious advantages in the treatment of recurrent / metastatic head and neck squamous cell carcinoma, but the overall response rate is less than 20% and the efficiency of immunotherapy for head and neck squamous cell carcinoma need to be improved urgently. This study firstly found abnormally high expression of ENPP1 in head and neck squamous cell carcinoma , together with low expression of CD8 + T cells; In vitro study indicate that ENPP1 hydrolyze extracellular cGAMP. ENPP1 as an extracellular enzyme, its substrate cGAMP and hydrolysate adenosine both play important roles in tumor immune regulation. Therefore, we hypothesize that ENPP1 is an important regulator for head and neck squamous cell carcinoma immunity, and targeted inhibition of ENPP1 may be a noval strategy for head and neck squamous cell carcinoma immunotherapy. This research intends to study the role and mechanism of ENPP1 in immunosuppression of head and neck squamous cell carcinoma by cGAS-STING and adenosine pathways using a head and neck epithelial specific ENPP1 gene knockout mouse and in vitro experiments. We will also study the effect of ENPP1 inhibitor alone or together with PD-L1 antibody on immunotherapy. The research will provide a noval strategy and target for improving the immunotherapy efficiency for head and neck squamous cell carcinoma.