Genomic ERBB2/ERBB3 mutations promote PD-L1-mediated immune escape in gallbladder cancer: a whole-exome sequencing analysis. Issue 6 (28th June 2018)

• Record Type: Journal Article
• Authors: Li, Maolan; Liu, Fatao; Zhang, Fei; Zhou, Weiping; Jiang, Xiaoqing; Yang, Yuan; Qu, Kai; Wang, Yueqi; Ma, Qiang; Wang, Ting; Bai, Lu; Wang, Zheng; Song, Xiaoling; Zhu, Yidi; Yuan, Ruiyan; Gao, Yuan; Liu, Yongchen; Jin, Yunpeng; Li, Huaifeng; Xiang, Shanshan; Ye, Yuanyuan; Zhang, Yijian; Jiang, Lin; Hu, Yunping; Hao, Yajuan; Lu, Wei; Chen, Shili; Gu, Jun; Zhou, Jian; Gong, Wei; Zhang, Yong; Wang, Xuefeng; Liu, Xiyong; Liu, Chang; Liu, Houbao; Liu, Yun; Liu, Yingbin;
• Is Part Of: Gut. Volume 68:Issue 6(2019)
• Page Start: 1024
• Page End: 1033
• Publication Date: 2018-06-28
• Subjects: gallbladder carcinoma -- whole-exome sequencing -- ERBB2/ERBB3 -- Programmed death-ligand 1(PD-L1); Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2018-316039
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : Objectives: Patients with gallbladder carcinoma (GBC) lack effective treatment methods largely due to the inadequacy of both molecular characterisation and potential therapeutic targets. We previously uncovered a spectrum of genomic alterations and identified recurrent mutations in the ErbB pathway in GBC. Here, we aimed to study recurrent mutations of genes and pathways in a larger cohort of patients with GBC and investigate the potential mechanisms and clinical significance of these mutations. Design: We performed whole-exome sequencing (WES) in 157 patients with GBC. Functional experiments were applied in GBC cell lines to explore the oncogenic roles of ERBB2 / ERBB3 hotspot mutations, their correlation with PD-L1 expression and the underlying mechanisms. ERBB inhibitors and a PD-L1 blocker were used to evaluate the anticancer activities in co-culture systems in vitro and in vivo. Results: WES identified ERBB2 and ERBB3 mutations at a frequency of 7%–8% in the expanded cohort, and patients with ERBB2 / ERBB3 mutations exhibited poorer prognoses. A set of in vitro and in vivo experiments revealed increased proliferation/migration on ERBB2 / ERBB3 mutation. Ectopic expression of ERBB2/ERBB3 mutants upregulated PD-L1 expression in GBC cells, effectively suppressed normal T-cell-mediated cytotoxicity in vitro through activation of the PI3K/Akt signalling pathway and contributed to the growth and progression of GBC in vivo. Treatment with an ERBB2/ERBB3 inhibitor or a PD-L1 monoclonal antibody reversed these immunosuppressive effects, and combined therapy revealed promising therapeutic activities. Conclusions: ERBB2 / ERBB3 mutations may serve as useful biomarkers in identifying patients who are sensitive to ERBB2/ERBB3 inhibitors and PD-L1 monoclonal antibody treatment. Trial registration number: NCT02442414 ;Pre-results.