抑制FGF19/FGFR4信号通路促进肺鳞癌细胞焦亡及免疫增效的机制研究

实现肿瘤局部“冷-热”转换，是提高免疫检查点抑制剂(ICIs)抗肿瘤效应，扩大ICIs临床获益人群的重要手段。作为肺鳞癌潜在的治疗靶标，FGF19/FGFR4促进肺鳞癌的发生发展，但其与免疫细胞的浸润是否相关尚不清楚。我们最近的研究表明特异性抑制FGF19下游STAT3通路可以抑制PD-L1的表达。此外， 焦亡蛋白GSDMB/GSDME在肺鳞癌细胞的启动子区域高甲基化，而FGFR4的特异性抑制剂FGF401可上调GSDMB/GSDME，诱导肿瘤细胞焦亡，促进免疫浸润。本项目拟在上述研究基础上，以FGFR4靶向治疗为抓手，深入探究抑制FGFR4诱导焦亡、重塑肿瘤微环境的分子机制，并寻找其诱导的特异性免疫细胞，以崭新视角揭示FGF19/FGFR4通路在肿瘤微环境中扮演的角色，建立FGF401联合ICIs协同治疗的路径。相关研究成果将为临床上不能从ICIs单药获益的肺鳞癌患者提供一定的指导意义。

The illustration of "cold-hot" tumor characteristics is of great value to explore new strategies to enhance the clinical efficacy of immune checkpoint inhibitors (ICIs) and expand the beneficiary population. As a potential therapeutic target in lung squamous carcinoma, FGF19/FGFR4 promotes the progression of lung squamous carcinoma. However, little is known about the relationship between FGF19 expression and the infiltration of immune cells. In our unpublished, preliminary study, we have found out FGF401, an inhibitor of FGFR4, could decrease PD-L1 expression by inhibiting the phosphorylation of STAT3. Moreover, inhibition of FGFR4 could induce tumor cell pyroptosis and promotes immune infiltration through up-regulation of GSDMB/GSDME, which are hypermethylated in the promoter region of lung squamous carcinoma cells. Therefore, in this project, we will focus on the molecular mechanism of FGF401-induced pyroptosis, to ascertain whether a subpopulation of immune cells in the tumor microenvironment plays a crucial role and design a combination therapy with existing ICIs and FGFR4 inhibitors. These investigations will provide theoretical evidence on new combinational therapy with FGF19 highly expressed Chinese squamous cell lung cancer patients.