ZDHHC17介导的PD-L1棕榈酰化修饰促进口腔白斑病免疫逃逸的机制和功能研究

口腔黏膜白斑病是癌前病变的代表疾病，将肿瘤免疫检查点的治疗“关口”前移至癌前病变阶段具有重要研究意义。我们前期研究发现PD-L1在人和小鼠口腔白斑组织中明显上调，PD-1单抗可有效治疗小鼠早期舌白斑病，但是部分小鼠对免疫治疗不应答和免疫逃逸的机制亟待研究。于是，我们从PD-L1蛋白翻译后修饰角度鉴定出白斑表达PD-L1的特异性位点存在棕榈酰化修饰和特异性棕榈酰化酶ZDHHC17。申请人据此提出科学假说：ZDHHC17介导口腔白斑病表达PD-L1特异性位点的棕榈酰化修饰促进PD-1治疗的免疫逃逸。通过本项目研究将揭示ZDHHC17对白斑细胞增殖的促进作用及机制，明确ZDHHC17介导PD-L1的棕榈酰化特异性位点修饰功能，探索棕榈酰化抑制剂2-BP联合PD-1单抗治疗白斑病的可行性。本项目旨在研究针对PD-L1治疗口腔癌前病变免疫逃逸的机制，以期为全身癌前病变免疫预防精准治疗研究提供新策略。

Oral leukoplakia is a representative disease of precancerous lesions. It is of great research significance to advance the treatment of tumor immune checkpoints to the stage of precancerous lesions. Our previous studies found that PD-L1 is significantly up-regulated in human and mouse oral leukoplakia tissues. PD-1 monoclonal antibody can effectively treat early leukoplakia in mice, but the mechanism of some mice that do not respond to immunotherapy and immune escape is urgently needed to be studied. Therefore, from the perspective of post-translational modification of PD-L1 protein, we identified the presence of palmitoylation modification and the specific palmitoylase ZDHHC17 at the specific site of PD-L1 expression in leukoplakia. Based on this, a scientific hypothesis was put forward, palmitoylation transferase ZDHHC17 mediates the palmitoylation modification of the specific site of PD-L1 expression in oral leukoplakia, and promotes the immune escape of oral leukoplakia treatment. The research of this project will reveal the promoting effect and mechanism of ZDHHC17 on the proliferation of leukoplakia cells, clarify the specific site modification function of PD-L1 mediated by ZDHHC17, and explore the feasibility of palmitoylation inhibitor 2-Bromopropane combined with PD-1 monoclonal antibody in the treatment of oral leukoplakia. This project aims to study the mechanism of immune escape for the treatment of oral precancerous lesions with PD-L1, in order to provide a new basis for the research of precision treatment of systemic precancerous lesions.