ERBB3-V104L通过上调PD-L1表达促进胆囊癌免疫逃逸的作用及其调控机制研究

靶向PD-1/PD-L1免疫检查点治疗在多种肿瘤中显示出明显的疗效，但是其介导的免疫逃逸在胆囊癌中的作用及调控机制尚属空白。我们前期发现ERBB3在胆囊癌病人中发生高频突变，其中V104L是突变的热点区域；ERBB3-V104L可促进胆囊癌的增殖能力，并可上调PD-L1的表达，提示ERBB3-V104L在胆囊癌发生发展中发挥重要功能，并与胆囊癌免疫逃逸相关。据此我们提出假说，ERBB3-V104L通过上调PD-L1的表达，促进微环境中杀伤性T细胞耗竭，从而负性调控机体的免疫应答，导致胆囊癌免疫逃逸的发生。本课题拟从分子、细胞、组织以及动物水平等多层次揭示ERBB3-V104L通过上调PD-L1影响胆囊癌T细胞免疫逃逸的分子机制；进一步研究联合靶向ERBB3及PD-L1对胆囊癌的治疗价值。本课题将为胆囊癌发生、发展及免疫逃逸机制提供新的研究基础，为胆囊癌靶向治疗联合免疫治疗提供理论依据。

The treatment targeting PD-1/PD-L1 showes obvious curative effect in a variety of carcinoma, nevertheless, PD-L1 expression and regulatory mechanism in gallbladder carcinoma is still elusive. Our previous study analyzed exome sequence from GBC tumors and identified that non-silent ERBB3 mutations are frequent events in gallbladder cancer patients. Additionally, we found that V104L mutation is the hottest spot among these non-silent mutations. Furthermore, the mutant of ERBB3-V104L can significantly promote the ability of GBC cells to proliferate and metastasis. Most importantly，V104L mutant could upregulate the PD-L1 expression level in GBC cells. These indicate ERBB3-V104L mutant play a key role in immune escape in the process of GBC progression. Thus we hypothesize that ERBB3-V104L mutant upregulates PD-L1 expression in GBC cells and promotes T cell apoptosis to inhibit CD4, CD8 T cell activation and proliferation, which negatively regulate the immune response and result in immune escape of GBC. This study aims to clarify the role of ERBB3-V104L in the immune escape of GBC and to explore the regulatory mechanism of PD-L1 expression using various systems including molecular, cellular, tissue and animal models.. This study will also provide theoretical basis for the potential using of ERBB3-V104L and PD-L1 as a new target for gallbladder cancer treatment which combining immunotherapy and targeted therapy and will shed light on the future treatment of gallbladder cancer.