TY - JOUR T1 - Genomic <em>ERBB2</em>/<em>ERBB3</em> mutations promote PD-L1-mediated immune escape in gallbladder cancer: a whole-exome sequencing analysis JF - Gut JO - Gut SP - 1024 LP - 1033 DO - 10.1136/gutjnl-2018-316039 VL - 68 IS - 6 AU - Maolan Li AU - Fatao Liu AU - Fei Zhang AU - Weiping Zhou AU - Xiaoqing Jiang AU - Yuan Yang AU - Kai Qu AU - Yueqi Wang AU - Qiang Ma AU - Ting Wang AU - Lu Bai AU - Zheng Wang AU - Xiaoling Song AU - Yidi Zhu AU - Ruiyan Yuan AU - Yuan Gao AU - Yongchen Liu AU - Yunpeng Jin AU - Huaifeng Li AU - Shanshan Xiang AU - Yuanyuan Ye AU - Yijian Zhang AU - Lin Jiang AU - Yunping Hu AU - Yajuan Hao AU - Wei Lu AU - Shili Chen AU - Jun Gu AU - Jian Zhou AU - Wei Gong AU - Yong Zhang AU - Xuefeng Wang AU - Xiyong Liu AU - Chang Liu AU - Houbao Liu AU - Yun Liu AU - Yingbin Liu Y1 - 2019/06/01 UR - http://gut.bmj.com/content/68/6/1024.abstract N2 - 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. ER -