和胃消瘤方通过PROX1/IFN-γ通路促进M1型巨噬细胞分化协同PD-1抑制剂治疗胃癌的机制研究

Gastric cancer is a common malignant tumor of the digestive system,the immunotherapy has been applied to the treatment of advanced gastric cancer, numerous studies have shown that tumor immune microenvironment heterogeneity determines the effect of immunotherapy. Studies have shown that changing the function of macrophages can reshape the immune microenvironment and enhance the efficacy of immunotherapy. Our previous study have found that He Wei Xiao Liu Fang(HWXL) could improve the clinical symptoms of advanced gastric cancer. Animal experiments have found that combine PD-1 inhibitors could inhibit tumor growth and increase the proportion of M1-type macrophages in tissues. HWXL containing serum could reduce the expression of PROX1 gene in gastric cancer cells. So we speculate that HWXL may play a synergistic antitumor effect with PD-1 inhibitors by blocking the NF-κB pathway,down-regulating PROX1 expression,prompting IFN-γ expression, promote the M1 macrophages differentiation, reshape the tumor immune microenvironment. In this study, we observe the effects of HWXL and/or PD-1 inhibitors on the growth of gastric cancer cells and the effects on macrophages differentiation, and observe whether HWXL containing serum promote IFN-γ expression through a PROX1-dependent mechanism,and observe the effect of HWXL containing serum on the expression of IFN-γ in gastric cancer cells on macrophage differentiation, defining the signal pathway of HWXL regulating PROX1 expression,to clarify its mechanism.

胃癌是常见的消化系统恶性肿瘤，目前免疫治疗已应用于进展期胃癌的治疗，诸多研究表明肿瘤免疫微环境的异质性决定了免疫治疗的疗效，改变巨噬细胞的功能可以重塑免疫微环境，增强免疫治疗的疗效。我们的前期研究发现和胃消瘤方可以改善晚期胃癌患者的临床症状，动物实验发现联合PD-1抑制剂可以抑制肿瘤的生长，并提高组织中M1型巨噬细胞比例，可以下调胃癌细胞PROX1（同源异型蛋白）基因的表达。因此我们推测和胃消瘤方可能通过阻断NF-κB信号通路，下调PROX1的表达，促使IFN-γ表达增多，促进M1型巨噬细胞分化，从而与PD-1抑制剂发挥协同抗肿瘤作用。本研究通过观察和胃消瘤方和/或PD-1抑制剂对胃癌细胞影响和对巨噬细胞分化的影响、观察其是否通过PROX1依赖性机制促进IFN-γ表达、并观察其促进IFN-γ表达对巨噬细胞分化的影响，明确调控PROX1表达的信号通路，初步阐明其作用机制。

胃癌是常见的消化系统恶性肿瘤，目前免疫治疗已应用于进展期胃癌的治疗，诸多研究表明肿瘤免疫微环境的异质性决定了免疫治疗的疗效，改变巨噬细胞的功能可以重塑免疫微环境，增强免疫治疗的疗效。我们的前期研究发现和胃消瘤方可以改善晚期胃癌患者的临床症状，动物实验发现联合 PD-1抑制剂可以抑制肿瘤的生长。本研究通过构建胃癌移植瘤模型，证实和胃消瘤方能够提高PD-1抑制剂的疗效，协调发挥抗肿瘤作用，延缓胃癌的恶性进展；体外实验通过 MTT 实验、流式细胞术、Transwell、real-time PCR和Western blotting及基因测序等方法，提示和胃消瘤方含药血清可以抑制胃癌细胞的增殖，能够通过胃癌细胞上清促进巨噬细胞向M1型分化，其具体机制可能在于阻断NF-κB信号通路，下调PROX1的表达，从而促使IFN-γ表达增多，从而促进肿瘤微环境中的单核细胞向抗肿瘤的M1型巨噬细胞分化，重塑肿瘤免疫微环境，为中药复方提高胃癌免疫治疗有效率提供新的依据。

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